Engineering Bi₂S₃-based nanoreactors for antimicrobial applications: synthetic strategies, mechanistic insights, and practical implementations

Abstract

Bacterial infections pose a critical threat to global public health, but the overuse of antibiotics exacerbates antimicrobial resistance, urgently necessitating alternative antibacterial strategies. Nanoreactors, as innovative nanoplatforms capable of generating antibacterial effects through physical or chemical mechanisms independent of traditional antibiotics, offer a viable pathway to circumvent such resistance. This review systematically examines recent advances in Bi₂S₃-based nanoreactors for antibacterial applications, covering synthesis methods, modification strategies, antibacterial mechanisms, and potential uses. A key challenge lies in enhancing Bi₂S₃-based nanoreactors’ catalytic activity and biocompatibility under physiological conditions. It highlights that tailoring the morphology and electronic structure (doping, defect engineering or heterojunction construction) can effectively bolster the antibacterial efficacy of Bi₂S₃. The review further emphasizes the multiple antibacterial mechanisms of Bi₂S₃-based nanoreactors, including physical damage, chemical action and immunomodulatory effects, which boast advantages such as high efficiency, low toxicity, and multi-functional synergy. This work seeks to comprehensively synthesize the current state of Bi₂S₃-based nanoreactors in antibacterial applications, while identifying key challenges in optimizing synthesis processes, enhancing stability, and advancing clinical translation. Moreover, it underscores the potential of Bi₂S₃-based nanoreactors as a next-generation antibacterial agent, offering theoretical frameworks to facilitate its clinical adoption and innovative solutions to address the global antibiotic resistance crisis.

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1. Introduction

Bacterial infection is one of the greatest threats to global public health, seriously endangering public health and life. In recent decades, bacterial infections have ranked among the main causes of human death.^1,2 According to the Global Burden of Disease study, a total of 13.7 million people died of bacterial infection in 2019.³ To date, antibiotics remain an effective therapy against pathogenic bacteria infection worldwide. Since the discovery of penicillin, scientists have developed a large number of antibiotics.^4–6 However, the large-scale use of antibiotics leads to bacterial variation and drug resistance.

Antibiotic resistance is a significant health challenge facing the world in the 21st century. Studies estimated that 4.71 million (95% of UI 4.23–5.19) deaths in 2021 were associated with the global antimicrobial resistance burden (AMR), of which 1.14 million were due to AMR. According to relevant studies, if not effectively controlled, the AMR burden is expected to increase to 1.91 million.^7,8 The limitations of traditional antibiotics exacerbated the crisis, especially due to the low efficiency of biofilms. A biofilm is a three-dimensional environmental adaptation structure formed by bacteria: an extracellular polysaccharide matrix encapsulates bacteria, which not only physically blocks antibiotics, but also reduces metabolic activity through gene regulation, significantly weakening drug sensitivity. Clinically, more than 65% of chronic bacterial infections (such as prosthetic joint infections, chronic pneumonia) involve biofilms. The recurrence rate of such infections is high, which significantly increases mortality and medical costs, while traditional antibiotic mechanisms (such as inhibiting cell wall/protein synthesis) find it difficult to break through the multi-drug resistance barrier of biofilms. At the same time, the spread of AMR makes some “super bacteria” resistant to ultimate drugs such as polymyxin, which greatly limits the treatment options. Therefore, novel antibiotics that effectively target biofilm bacteria are urgently needed.^9–11

The existing antibiotic R&D pipeline is weak, further worsening the situation. From 2020 to 2022, only two new Gram-positive bacteria-targeted antibiotics were approved worldwide. Candidate drugs for the clinical stage include: 47 direct-acting antimicrobial agents, 5 non-traditional small molecule drugs, and 10 combinations of β-lactamase inhibitors. However, more than 80% are in phase I/II, and the specific drugs targeting biofilm are less than 5%.¹² Based on the above challenges, it is urgent to develop a new generation of antibacterial drugs that can simultaneously break through the AMR and biofilm barriers. The antibacterial mechanisms of antibiotics include inhibition of bacterial cell wall synthesis, enhancement of bacterial cell membrane permeability, interference with bacterial protein synthesis, and inhibition of bacterial nucleic acid replication and transcription. Similar to antibiotics, nanocomposites can not only affect the structure and composition of bacteria but also bring significant advantages to antibacterial treatment through physical and chemical disinfection mechanisms. This requires us to combine materials science and nanotechnology to develop new preparations with targeted delivery and environmental response functions to meet severe clinical challenges.^13,14

Bismuth (Bi), as a low-toxicity heavy metal, has a long history of application in the field of antibacterials, which can be traced back to the 18th century. In the early stage, preparations with colloidal bismuth as the core component, such as bismuth subnitrate and bismuth subcarbonate, were widely used in the adjuvant treatment of gastrointestinal infections. The antibacterial mechanism is mainly based on the unique chemical properties of Bi³⁺. Bi³⁺ can specifically bind to the thiol groups on the bacterial cell wall. This binding will destroy the integrity of the bacterial cell membrane, damage the barrier function of the cell membrane, and the substances inside the bacteria are easy to leak, thus affecting the normal physiological activities of the bacteria.^15–17

The breakthroughs in nanotechnology in the 21st century brought opportunities for the innovation of bismuth-based materials. With advancing technology, bismuth-based materials are evolving towards nanoscale and functionalization. In terms of zero-dimensional structure, as a promising antibacterial material, the antibacterial mechanism of Bi₂O₃ is closely related to its structure and physicochemical properties, but there are also some deficiencies in its application.^18–20 In the field of two-dimensional materials, BiOX (X = Cl, Br, I) exhibits a unique antibacterial mechanism.^21–23 The high-exposed crystal planes and porous structure of two-dimensional nanosheets (such as BiOBr) can enhance carrier separation efficiency, increase specific surface area, and promote bacterial adsorption and ROS diffusion. However, nano-sized BiOX materials are prone to accumulate in the body, posing potential risks of toxic side effects. Therefore, designing nanoreactors with degradable properties and easy metabolism is of great significance. Bi₂S₃-based nanoreactors refer to a nano system that can achieve the integration of “reactant enrichment-catalytic reaction-product release” through precise control of size, morphology and surface structure. Its core advantage lies in its high specific surface area, abundant surface active sites, and responsiveness to external stimuli such as light and heat, which can efficiently mediate antibacterial reactions such as photothermal, photodynamic, and ion release. Heterogeneous structured bismuth-based nanoreactors achieve this by constructing p-n heterojunctions (HJs) or dual S-shaped heterostructures to form internal electric fields, which accelerate the separation of photogenerated electrons (e⁻) and holes (h⁺).^24,25 This series of evolutions from colloidal bismuth to nanostructured bismuth-based materials reveals that the nanosized bismuth-based materials not only improve the antibacterial efficiency but also reduce the amount of bismuth and promote the upgrade iteration of bismuth-based materials (Fig. 1). This development lay a solid theoretical foundation for the rational design of bismuth sulfide (Bi₂S₃) in the field of antibacterial and anti-infection, enabling researchers to develop more efficient and low-toxic bismuth-based antibacterial materials. Among various bismuth-based materials, Bi₂S₃ stands out due to its unique properties and becomes a new focus in the research on antibacterial and anti-infection:

Fig. 1 Summary of the development of Bi₂S₃-based nanoreactors in the antibacterial field from 2016 to 2025.

(1) Bi₂S₃ belongs to the orthorhombic crystal system, and its crystal structure can be regarded as a quasi-one-dimensional arrangement of (Bi₄S₆)_n bands held together by van der Waals forces.²⁶ This structure endows Bi₂S₃ with some special properties. For instance, the relatively weak van der Waals forces between layers enable ions or molecules to be more easily inserted between the layers, thereby achieving performance control in certain applications. Moreover, the arrangement of bismuth and sulfur atoms in the structure affects the electron transport and distribution, exerting a significant influence on its electrical and optical properties.

(2) Bi₂S₃ exhibits excellent photothermal conversion properties, enabling rapid temperature increase under near-infrared (NIR) light irradiation, thereby disrupting the structure of bacterial cell membranes and achieving efficient antibacterial effects. For instance, the Zn-CN/P-GO/BiS nanocomposite, after being exposed to 808 nm NIR (0.67 W cm⁻²) for 20 min, could reach a temperature of up to 55.2 °C, demonstrating its outstanding photothermal properties.²⁷ Moreover, Bi₂S₃ has a narrow band gap (approximately 1.3–1.7 eV) and a large specific surface area, which can provide more surface-active sites for photocatalytic reactions, absorb visible light and generate photogenerated electron–hole pairs to generate reactive oxygen species (ROS) with strong oxidizing properties, thereby damaging the cell membranes and internal structures of bacteria. For example, Abdel-Moniem et al. significantly improved the photocatalytic antibacterial efficiency by constructing a Bi₂S₃@g-C₃N₄ heterostructure, demonstrating excellent antibacterial effects against various bacteria.²⁸

(3) Bi₂S₃ nanoparticles (NPs) exhibit excellent biocompatibility and stability, good stability in the physiological environment, and are not easy to agglomerate or degrade. In addition, their surfaces can be modified by biomolecules (such as starch, chitosan, etc.) to further improve biocompatibility and reduce toxicity toward normal cells. This feature makes them have broad prospects in biomedical applications.²⁹ More importantly, Bi₂S₃ exhibits low toxicity and safety. The cytotoxicity of Bi₂S₃ nanocrystals is relatively low and it is generally regarded as a biologically safe and environmentally friendly material, with an LD₅₀ of 100 mmol L⁻¹. Its safety is comparable to that of therapeutic iodine-based drugs.³⁰ This characteristic makes its application in the biomedical field more advantageous than other antibacterial materials, reducing potential harm to the human body and providing a guarantee for its use in antibacterial treatment.

In the face of the increasingly severe challenge of AMR and the numerous limitations of traditional antibiotics, Bi₂S₃-based nanoreactors stand out due to their unique advantages and become a research hotspot in the antibacterial field. Delving into their synthesis and nanotechnology strategies, analyzing the antibacterial mechanism, and clarifying their application scenarios in various antibacterial situations not only help to comprehensively understand the antibacterial performance of these materials, but also provide a solid theoretical foundation for further optimization and expansion of their applications. Based on this, this article will elaborate in detail on the synthesis methods, antibacterial mechanisms, and applications of Bi₂S₃-based nanoreactors in resistant bacterial infections, medical device-related infections, and combined antibacterials, aiming to provide valuable references for promoting the development and clinical application of Bi₂S₃-based antibacterial nanoreactors.

2. The synthesis method of Bi₂S₃

Nanoreactors are materials with sizes in the range of 1–100 nm, with unique structural, optical, electrical, thermal and magnetic properties. Its advantages are due to its high specific surface area and excellent performance in catalysis, sensing, energy conversion and other fields. For example, it can be used for photocatalytic decomposition of pollutants, magnetic drug delivery and other applications.³¹ The synthesis methods mainly include bottom-up and top-down methods (Fig. 2). Bottom-up organic ligand-assisted growth, such as organic ligand-assisted growth, can accurately control the size and shape of nanoreactors through ligand-controlled crystal growth, and the products have good dispersion; top-down methods such as mechanical compression can obtain ultra-thin nanosheets from bulk metals, and the operation is relatively direct.³²

Fig. 2 (a) Schematic diagram of the synthesis of Bi₂S₃ nanoreactors using a solvothermal method. (b) A schematic diagram of the synthesis of Bi₂S₃ nano-single crystals by chemical vapor deposition. (c) A schematic diagram of the synthesis of Bi₂S₃ nanoreactors using a biological template method.

Bi₂S₃ is mainly prepared by direct elemental reaction, chemical deposition and thermal decomposition of bismuth complexes with sulfur ligands (Table 1). However, most of the Bi₂S₃ prepared by these methods have poor crystallinity or contain impurities. The emergence of solvothermal methods provides a solution for the preparation of nano-sized Bi₂S₃. The solvothermal method regulates the size and shape of NPs. The high-pressure environment promotes the orderly arrangement of the lattice, and the product has high crystallinity, but this method relies on the high energy consumption of the equipment. Chemical vapor deposition further improves crystal quality by delivering bismuth and sulfur precursors in the gas phase onto a heated substrate. Under precisely tuned temperature and pressure, atoms assemble layer-by-layer, yielding compact films or single-crystal nanowires with near-defect-free lattices. The technique excels in pattern fidelity and electronic-grade purity, yet it demands high vacuum, corrosive carrier gases, and energy-intensive heating, restricting scale and sustainability. In contrast, biosulfur-driven green synthesis operates at ambient pressure and near-physiological temperature. Living systems – ranging from microbial cultures to plant-derived peptides – liberate reactive sulfide through natural metabolism, while surface functional groups template and stabilize growing Bi₂S₃ crystals. The process avoids toxic solvents, high temperature, and external sulfur reagents, offering an energy-efficient, scalable route to well-defined nanostructures with tunable morphology.

Table 1 Advantages and disadvantages of Bi₂S₃ preparation routes

Synthetic route	Advantages	Disadvantages	Ref.
Thermal decomposition of sulfur–ligand bismuth complexes	Single-source precursor ensures exact stoichiometry; low decomposition temperature (200–450 °C)	Multi-step precursor synthesis increases costs; requires inert atmosphere; scale-up limited by precursor availability	33
Direct elemental reaction	Simplest process: only Bi and S; atomic-level stoichiometry	High equipment costs: elevated temperature (>400 °C) and vacuum required	34
Solvothermal method	Low operating temperature (100–220 °C)	Requires autoclave; possible solvent or surfactant residues; post-synthetic purification needed	35,36
Chemical vapor deposition	Uniform, dense thin films; direct growth on various substrates; controllable thickness and orientation	High equipment costs: elevated temperature (>400 °C) and vacuum required	40,41
Biosulfur-driven synthesis	Green and sustainable, uses sulfur-containing amino acids/proteins	Lower crystallinity: organic residues require post-treatment	48,49

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2.1. Solvothermal method

The core advantage of the solvothermal method is that it realizes the control of material design and synthesis that is difficult to achieve by traditional methods through solvent engineering and mild high-pressure conditions in a closed system. This method uses the polarity, coordination ability and redox properties of the solvent to accurately regulate the reaction path, crystal phase and morphology of the product. Mild temperature (usually <400 °C) combined with self-generated high pressure significantly improves the solubility and diffusion rate of the precursor and stabilizes the metastable and open-framework hybrid materials while suppressing the thermodynamic phase transition. Its closed system effectively reduces the release of volatile by-products, especially suitable for the controllable preparation of non-oxides (nitrides, chalcogenides) and nano-functional materials, providing an efficient and flexible synthetic route for the development of advanced materials.³⁷

Leveraging the unique solvent-dominated reaction environment described above, solvothermal synthesis has been widely adopted to fabricate Bi₂S₃ nanoreactors with tailored morphologies. Yu et al. used BiCl₃ and Na₂S·9H₂O as raw materials and EDTA as the complexing agent to obtain rod-like Bi₂S₃ powder by solvothermal treatment in alkaline sol.³⁵ Similarly, Yang et al. proposed a simpler method by mixing Bi(NO₃)₃·5H₂O with ethanol and adding it to CS₂ to obtain Bi₂S₃ nanorods. If ethanol is replaced with H₂O, nanosheets will be obtained. This shows that ethanol is involved in the regulation of growth direction.³⁶ The solvothermal method can also synthesize nanoreactors with different morphologies. Wang et al. used Bi(NO₃)₃·5H₂O and thioacetamide as raw materials and dimethylformamide (DMF) as the solvent, and synthesized Bi₂S₃ nanoreactors by surfactant SUDEI. If SUDEI is not added to DMF, most of the Bi₂S₃ will form tapered nanorods that gradually become thinner. When the concentration of SUDEI is 2 g L⁻¹, a double-headed cauliflower-like structure can be formed, which is assembled by nanorods with a length of 300–500 nm and a diameter of 10–30 nm. If the concentration of SUDEI increases to 6 g L⁻¹ or higher, it will be transformed into a single head cauliflower or even a spherical structure. There are significant differences in the sensing properties of nano-sized Bi₂S₃ particles with different morphologies for simultaneous determination of dopamine and ascorbic acid. The sensing ability of cauliflower-like Bi₂S₃ is better than that of rod-like Bi₂S₃, which may be attributed to its porous/spacing structure and the large surface area of cauliflower-like Bi₂S₃.³⁸

The solvothermal method enables the fabrication of diverse Bi₂S₃ nanoreactors, ranging from 2D nanosheets to complex 3D structures. Jin et al. synthesized the pine-like Bi₂S₃ structure by the solvothermal method. They dissolved Bi(NO₃)₃·5H₂O and thiourea in water, added thioglycolic acid, and mixed with tetrahydrofuran. The reaction was carried out at 160 °C for 9 hours to obtain the product. The multi-scale morphology characterization low magnification field emission scanning electron microscopy (FESEM) image of the product is shown in Fig. 3a. The scanning electron microscope (SEM) panoramic view clearly presents the unique three-dimensional pine-like hierarchical structure. Further high-magnification SEM observation (Fig. 3b) reveals that this structure is composed of many nanosheets, with an average thickness of 110 nm, a width of 2 µm, and a length of 15 µm. The material has a specific surface area of 15.32 m² g⁻¹. The structural analysis indicates that these nanosheets are composed of secondary nanowires or nanobelt arrays. The high-resolution transmission electron microscope (HRTEM) results in Fig. 3c from the atomic scale confirms the structural essence: the clear lattice stripes of 0.786 nm correspond to the [110] crystal plane of orthorhombic Bi₂S₃, and the Fourier transform diffraction pattern (inset) further verifies that it is a single crystal grown preferentially along the [001] direction.³⁹

Fig. 3 (a) Low-magnification field emission scanning electron microscopy (FESEM) image of Bi₂S₃. (b) High-magnification FESEM image of Bi₂S₃. (c) HRTEM image acquired at the sheet corner. Inset shows the corresponding Fourier transform pattern.³⁹ Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (d) TEM image of the highly ordered snowflake-like structures at low magnification. (e) and (f) TEM image of a single snowflake-like structure and its magnified close-up view.⁴⁸ Copyright 2004 American Chemical Society.

2.2. Chemical vapor deposition

Chemical vapor deposition (CVD) is a critically important material preparation technology that deposits thin layers or nanostructures on substrate surfaces through chemical reactions, enabling the fabrication of films with high-purity, dense, uniform, and strongly adherent characteristics.

The CVD method allows the preparation of Bi₂S₃ with varying dimensions on substrates of different materials. Rong et al. employed CVD to fabricate a hollow cross-linked network structure on fluorophlogopite mica, consisting of one-dimensional Bi₂S₃ nanobelts aligned along three specific orientations. This unique architecture enables multiple reflections of incident light between Bi₂S₃ nanobelts, resulting in remarkable light absorption effects.⁴⁰ Furthermore, the CVD technique facilitates the construction of mixed-dimensional heterostructures. Jiang et al. developed a two-step CVD epitaxial process to sequentially deposit 2D-WS₂ and 1D-Bi₂S₃ nanowires on C-plane sapphire substrates, forming a Bi₂S₃/WS₂ van der Waals heterostructure. The strong interfacial interaction between Bi₂S₃ and WS₂ promotes efficient transfer of photogenerated carriers at the heterojunction interface, significantly enhancing light-harvesting capabilities.⁴¹

CVD effectively synthesizes 2D-Bi₂S₃. Kim et al. grew ultrathin 2D Bi₂S₃ single crystals (∼9 nm thick, lateral dimensions up to tens of micrometers) on SiO₂/Si using Bi₂O₃ and H₂S gas, achieving exceptional optoelectronic performance due to strong Coulomb interactions.⁴² Separately, Atamtürk et al. used a single-source precursor (Bi (SBu^t)₃), sublimated at 100 °C and decomposed on silicon substrates at 250 °C, to generate 2D flake-like Bi₂S₃. Raman spectra confirmed structural anisotropy, with peak variations (e.g., 257 cm⁻¹ B_1g mode in horizontally aligned platelets) dependent on substrate orientation. Moreover, Bi₂S₃ on fluorine-doped tin oxide exhibited pronounced photoconductivity, including reproducible photoexcited carrier release and rapid response (rise time <4 s, decay time <9 s) under white light illumination.⁴³

2.3. Biosulfur-driven green synthesis

Biosulfur-driven green synthesis harnesses the innate sulfur metabolism of living systems to release reactive sulfide under mild aqueous conditions. Bismuth ions encounter these biogenic sulfides, leading to controlled nucleation and growth of crystalline Bi₂S₃. Peptides or entire microbial cells serve dual roles: they generate the sulfide and simultaneously template particle morphology through surface functional groups and extracellular proteins. The reaction proceeds at ambient temperature and pressure, eliminating the need for toxic reagents and high-energy inputs, thereby offering an energy-efficient and scalable route to advanced sulfide materials.^44–47

By dissolving Bi(NO₃)₃·5H₂O and glutathione (GSH) in water, Lu et al. obtained a highly ordered snowflake-like Bi₂S₃ under microwave irradiation. GSH is a polypeptide that can be used not only as an assembly agent, but also as a sulfur source. Bi³⁺ coordinates with carboxyl and amino groups on GSH, which controls the growth of Bi₂S₃. The thiol group on GSH decomposes during the reaction to provide sulfur. Fig. 3d demonstrates a highly ordered snowflake-like structure. Fig. 3e and f are transmission electron microscope (TEM) images with relatively high multiples, showing the single ordered structure and its selected area amplification image. It can be seen that this snowflake-like structure is formed by short and relatively long nanorods. The long nanorods grow radially from the center to the outside to form a hexagonal ordered structure. On these long nanorods, several short nanorods are grown from a center and arranged in an orderly manner to form a hexagonal structure similar to the snowflakes in nature, but highly ordered.⁴⁸

Microorganisms can likewise serve as sulfur sources, functioning as reactants in the synthesis. Kumar et al. prepared Bi₂S₃ by using Clostridium acetobutylicum and Bi₂(SO₄)₃. H₂S was released during the growth of Clostridium acetobutylicum. H₂S was used as a sulfur source to combine with Bi³⁺ to form Bi₂S₃, and the solution changed from yellow to dark brown. The product exhibits a unique hexagonal sheet-like structure. When centrifuged at 18 000 rpm, 6–10 nm small-sized particles were obtained, and 440–500 nm large-sized particles were obtained at 12 000 rpm. Therefore, the particle size can be flexibly controlled by centrifugal speed. These hexagonal nanostructures are similar to the layered manganese oxides prepared from bacterial-derived and naturally occurring burgherite. It can be seen from XRD and XPS analyses that the sulfate is completely reduced and pure Bi₂S₃ is obtained. Furthermore, the SDS-PAGE gel electrophoresis experiment directly confirmed that extracellular proteins from Clostridium acetobutylicum are present on the surface of the Bi₂S₃ NPs, acting as stabilizers. These proteins are used as natural stabilizers to prevent the agglomeration of NPs through steric hindrance or electrostatic interaction, replacing the artificial surfactants in traditional chemical synthesis. The unique mechanism of microbial “one bacterium and two effects” in biosynthesis is verified at the molecular level, which provides H₂S (reducing agent) and extracellular protein (stabilizer) at the same time, highlighting the sustainable advantages of this green synthesis route.⁴⁹ While the biological template method offers a promising avenue for sustainable nanoreactor synthesis, its practical application faces challenges including difficult extraction and purification of templates, high costs, low production yields, and difficulties in scaling up.

3. Modification strategy

Modification of nanoreactors (such as doping, defect engineering, and heterojunction construction) is the core strategy to improve their performance and expand their application range. These methods utilize the unique size effect and surface effect of nanoreactors to precisely control the structure and electronic properties of materials at the molecular level, thus bringing significant advantages. Introducing foreign atoms into the lattice of nanoreactors can accurately regulate their electrical and optical properties, create new catalytic activity centers, and enhance structural stability, providing core means for on-demand customization of material functions. Defect engineering at the nanoscale refers to the controllable introduction of defects such as vacancies and grain boundaries that can create highly active sites, change local electronic structures, and significantly improve the activity and efficiency of materials in catalysis, sensing, and ion storage. When nanoreactors with different energy band structures are combined to form heterojunctions, the photogenerated charges can be strongly separated by the built-in electric field at the interface, and the advantages of different components can be integrated, which is especially suitable for photo/electrocatalytic and optoelectronic devices.^50–52

3.1. Doping in the Bi₂S₃ lattice

Doping, defined as the intentional introduction of trace elements or impurities into a host material, constitutes a fundamental strategy for tailoring material properties and enhancing functional performance. The incorporation of foreign atoms perturbs the host lattice, resulting in modified energy band structures, modulated charge carrier concentrations, and engineered defect states. These synergistic effects collectively yield significant improvements in key characteristics, including elevated electronic/ionic conductivity, enhanced structural resilience, accelerated charge transfer kinetics, and extended electrochemical stability windows. The strategic application of doping proves particularly effective in nickel-doped Bi₂S₃ nanoreactors. Darji et al. studied the significant effects of nickel (Ni) doping on Bi₂S₃ nanoreactors in many aspects. From the perspective of structure, the lattice parameter and unit cell volume increase with the increase of doping amount after the successful incorporation of the Bi₂S₃ lattice due to the difference in ionic radius between Ni²⁺ and Bi³⁺. This change is accurately verified by Rietveld refinement of XRD. The doping changes the morphology of the Bi₂S₃ from the original nanocylinder to the nanotube or nanoparticle-containing composite structure. In terms of optical properties, by considering the direct allowed transitions of Ni_xBi_2−xS₃ (x = 0.0, 0.5, 1.0, 1.5 and 2.0 wt%) nanoreactors, the band gap is calculated using the Kubelka Munk function and energy diagram shown in Fig. 4a. The band gap of the original Bi₂S₃ is 1.55 eV, and it increases to 1.61 eV when the doping content is up to 2.0 wt%. This quantum confinement effect leads to the shrinkage of the size, which improves the separation efficiency of photogenerated electron–hole pairs. In terms of vibration characteristics, room temperature Raman spectroscopy (Fig. 4b) shows that no vibration peaks of 280–300 cm⁻¹ and 369–387 cm⁻¹ are observed in undoped Bi₂S₃; after Ni doping, a new vibration peak attributed to the Ni–S bond appears in these two intervals, and its intensity continues to increase with the increase in Ni doping amount (0.5 → 2.0 wt%) (Fig. 4d-e), which confirms that Ni²⁺ is successfully doped into the Bi₂S₃ lattice. Ni doping significantly enhanced the antibacterial activity of Bi₂S₃ against Gram-positive bacteria (such as Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (such as Serratia marcescens, Pseudomonas aeruginosa). As shown in Fig. 4c, 2.0 wt% Ni doping reduced the minimum inhibitory concentration (MIC) of Serratia marcescens from 70 µg mL⁻¹ to 55 µg mL⁻¹, and the antibacterial enhancement effect on Gram-negative bacteria was more prominent. It is speculated that it may be closely related to the increase of surface-active sites and the significant increase of ROS production efficiency. These multi-dimensional modification effects comprehensively and deeply reveal the excellent results of Ni doping in optimizing the structure and properties of Bi₂S₃ nanoreactors and greatly enhancing their antibacterial activity, which provides a valuable and important reference for the doping modification of metal chalcogenide nanoreactors.⁵³

Fig. 4 (a) Diffuse reflectance UV-Vis spectra presented as Kubelka–Munk transformed functions versus photon energy. (b) Concentration-dependent shifts of Raman active modes at room temperature for varying nickel content. (c) MIC values error bars against Staphylococcus aureus, Bacillus subtilis, Serratia marcescens, and Pseudomonas aeruginosa for Ni_xBi_2−xS₃ (x = 0.0, 0.5, 1.0, 1.5, 2.0 wt%) nanoreactors. (d) Room-temperature Raman spectra with Lorentzian peak fitting and identified Raman active modes. (e) Magnified spectral region highlighting the Ni–S vibrational mode.⁵³ Copyright 2022 Elsevier B.V.

3.2. Defect engineering

The introduction of bismuth vacancies and sulfur vacancies in the synthesis process can improve the light absorption capacity of Bi₂S₃, which greatly prolongs the lifetime of photogenerated electrons and achieves efficient charge separation. When surface defects are introduced on the surface of Bi₂S₃, these defects will prevent the charge from migrating to the surface-active sites. These defects further become the aggregation center of active charge and promote the interfacial reaction.⁵⁴ Regulating vacancies by controlling reaction time is also a common strategy for introducing vacancies.

By changing the solvent heat treatment time (1 h: BS-1; 3 h: BS-3; 5 h: BS-5), Bi₂S₃ nanorods with different defect types were prepared. The ESR spectrum (g ≈ 1.994) confirms that all samples have unpaired electron defects, and the XPS surface atomic ratio analysis Bi/S value: BS-1 is 0.72 greater than the theoretical value of 0.67, BS-3 is 0.59 less than the 0.67 binding energy shift, and BS-1 is determined to contain sulfur vacancies (S vacancies), BS-3 contains bismuth vacancies (Bi vacancies), and BS-5 is nearly defect-free. Both types of defects broaden the light absorption to NIR, both of which have excellent light absorption capacity and narrow the band gap (Bi vacancy: 1.45 eV; S vacancy: 1.62 eV). From the transient photoluminescence spectrum, it can be seen that Bi vacancies prolong the lifetime of photogenerated electrons to 1125.3 ps, inhibit electron–hole recombination, and reduce the conduction band potential to −0.76 V, which is conducive to the reduction of O₂ to ˙O₂⁻; the S vacancy shortens the carrier lifetime (638.3 ps), and the conduction band potential is only -0.33 V. The improvement of the separation efficiency of BS-3 is further confirmed by its steady-state photoluminescence spectrum, and its intensity is much weaker than that of BS-1 and BS-5, which verifies that the bismuth-deficient BS-3 exhibits better performance in separating photogenerated charges. In the scavenger experiment, it can be seen that the sterilization efficiency is significantly reduced after adding Cr(VI) to capture electrons, indicating that electrons are the dominant active species; the removal of holes by sodium oxalate resulted in a slight decrease in efficiency, indicating that holes have a secondary contribution. ROS are also deeply involved in the inhibition of bactericidal activity, as demonstrated by adding TEMPOL (trapping ˙O₂⁻), isopropanol (trapping ˙OH) and Fe³⁺-EDTA (trapping H₂O₂), respectively. Among them, the effects of ˙O₂⁻ and H₂O₂ are stronger than ˙OH. ESR direct detection further confirmed that under NIR irradiation (4 min), the surface of BS-3 can quickly generate ˙OH; the ˙O₂⁻ signal (g = 2.004) is detected after 6 min of irradiation, while no ROS signal is detected under dark conditions. This result is consistent with the scavenger experiment, indicating that the bismuth vacancy defect drives the reduction of O₂ to ˙O₂⁻ by promoting electron transfer, and then initiates the chain reaction to generate H₂O₂ and ˙OH, which synergistically destroys the bacterial structure. These active species synergistically attack the cell membrane of Escherichia coli (E. coli) to completely inactivate 7 log bacteria within 40 min, and the performance is much better than that of the S-vacancy samples.⁵⁵

3.3. Heterojunction construction

In general, a heterojunction refers to a special structure formed by two or more semiconductor materials with different electronic band structures in close contact at the interface. This structure can form band bending and a built-in electric field at the interface, which can significantly change the behavior of charge carriers. The energy band difference and the built-in electric field at the heterojunction interface will drive the photogenerated electrons and holes to migrate in the opposite direction and become enriched on different materials.⁵⁶ By physically separating electrons and holes, its life is greatly extended, so that it has more time to participate in surface catalytic reactions. Specifically, the construction of heterogeneous catalysts by introducing multiple components to form heterogeneous interfaces can effectively optimize the electronic structure, promote substrate enrichment, and regulate the microenvironment, thereby enhancing the catalytic advantages.⁵⁷

Shi et al. prepared a Bi₂S₃/SnIn₄S₈ heterojunction by a simple one-pot solvothermal method. By changing the ratio of Bi₂S₃ and SnIn₄S₈, a Z-type BS-SIS-2.5% heterojunction with a flower-like structure was obtained when the ratio of the two was 2.5%. The flower-like structure provides more contact interfaces and active sites, enabling better contact between the target material and the catalyst and enhancing the absorption of visible light. The BS-SIS-2.5% heterojunction has excellent photodegradation performance. Through the photocatalytic degradation of Rhodamine B (RhB) under visible light, there is almost no concentration change of RhB solution under visible light irradiation without adding catalyst. Compared with single Bi₂S₃ and SnIn₄S₈, the photocatalytic decomposition efficiency of RhB was significantly improved when the BS-SIS-2.5% heterojunction existed in the reaction system, and RhB was almost completely degraded within 48 min. BS-SIS-2.5% also has photocatalytic disinfection activity.

For SnIn₄S₈, the number of E. coli was significantly reduced after 5 h of light irradiation. For Bi₂S₃, the number of E. coli was almost not reduced, indicating that the photocatalytic disinfection activity of Bi₂S₃ was almost zero. Among all the samples, BS-SIS-2.5% has the strongest photocatalytic disinfection activity. When E. coli cells were treated with 30 mg BS-SIS-2.5% for 5 hours under visible light irradiation, E. coli cells were completely inactivated. Bi₂S₃/SnIn₄S₈ significantly accelerates the separation of photogenerated carriers through the band structure design, showing superior activity in degradation and bacterial inactivation. However, there are still limitations in the treatment of drug-resistant biofilm infections.⁵⁸

In order to achieve rapid healing of refractory infected wounds, Huang et al. proposed a novel H₂S-producing bio-heterojunction consisting of P-type CuS and N-type Bi₂S₃ loaded with lactate oxidase (LOx) utilizing polydopamine. As shown in Fig. 5a, Bi₂S₃ was synthesized by a one-step hydrothermal method followed by one-pot in situ CuS nanoparticle growth on the Bi₂S₃ surface to obtain the corresponding BC P–N bio-heterojunction. Subsequently, LOx was immobilized to the prepared heterojunction surface by the natural binder PDA to form a P–N bio-heterojunction (Bi₂S₃/CuS@PDA-LOx, abbreviated as BCPL) with H₂S generation ability. Fig. 5b–d illustrate the photothermal performance of the BCPL bio-heterojunction and its dependence on power. Fig. 5b shows that under NIR laser irradiation, the temperature increase of BCPL is significantly enhanced with the increase of power intensity, which clearly reflects the power-dependent characteristics of the photothermal effect. Fig. 5c further verifies its intrinsic performance in air: after 3 min of 1.0 W cm⁻² laser irradiation, the temperatures of Bi₂S₃@CuS (BC) and BCPL groups soared to 151 °C and 175 °C, respectively, while the PBS control group exhibited almost no change, confirming that BCPL has ultra-high photothermal conversion efficiency and can achieve efficient sterilization by denaturing bacterial proteins at high temperature. To simulate the physiological environment, Fig. 5d immersed BCPL in PBS for testing: under 808 nm NIR laser (1.0 W cm⁻²) irradiation, the temperature of the Bi₂S₃, CuS, BC and BCPL groups all increased significantly (CuS reached 65.9 °C, Bi₂S₃ was 61.2 °C, BC was about 59.1 °C), while the PBS group did not respond. It is worth noting that the mild warming of BC and BCPL (≈ 59 °C) can reduce the risk of healthy tissue damage while ensuring the bactericidal effect, providing a key basis for their biosafety. In terms of photodynamic performance, Fig. 5e–g jointly reveal the efficient ROS generation ability of BCPL. In Fig. 5e, through the methylene blue (MB) degradation experiment, it can be observed that under near-infrared light irradiation, the ˙OH generation ability of the BC heterojunction is significantly superior to that of Bi₂S₃ and CuS monomers. This is attributed to the unique heterojunction structure of BC, which can promote carrier separation. Fig. 5f uses 1,3-diphenylisobenzofuran (DPBF) as a probe to further detect singlet oxygen (¹O₂) an ˙O₂⁻, showing that the absorbance of DPBF in the BC group decreased most significantly, confirming that the heterojunction can efficiently capture ambient oxygen to generate a variety of ROS. The 3,3′,5,5′-tetramethyl benzidine (TMB) experimental results in Fig. 5g echo those in Fig. 5e, and the BC group ˙OH generation curve continues to rise, providing direct evidence for the photodynamic-chemic kinetic synergistic sterilization mechanism. Together, these results show that the BC heterojunction greatly improves ROS production through enhanced electron–hole separation efficiency, laying the foundation for efficient synergistic sterilization. In vitro assays show that both the self-built electric field of BCPL and H₂S generated in response to the infected microenvironment can upregulate the expression of angiogenic genes in the HIF-1 signaling pathway of L929 cells, which in turn significantly accelerates the biological processes of cell activity: proliferation, migration, and tube formation.⁵⁹

Fig. 5 (a) The formation of BCPL bio-HJs. (b) Temperature elevation of BCPL bio-HJs during NIR laser irradiation at different power intensities. (c) Temperature elevation of samples in air during NIR laser irradiation (808 nm, 1.0 W cm⁻²). (d) Temperature elevation of samples in PBS solution during NIR laser irradiation (808 nm, 1.0 W cm⁻²). (e) MB degradation by different samples under NIR light irradiation. (f) DPBF degradation by different samples. (g) TMB oxidation by different samples under NIR laser irradiation.⁵⁹ Copyright 2023 Wiley-VCH GmbH.

This section focuses on the core modification strategies of Bi₂S₃-based nano-reactors, achieving performance regulation through lattice doping, defect engineering, and heterostructure construction: Ni doping alters lattice parameters and morphology, enhancing carrier separation efficiency and reducing the MIC of Gram-negative bacteria; Bi vacancies prolong the lifetime of photogenerated electrons, promoting the generation of ROS, and efficiently inactivating Escherichia coli; Z-type/p–n type heterojunctions (such as Bi₂S₃/SnIn₄S₈, Bi₂S₃/CuS) utilize the built-in electric field to accelerate charge separation, strengthening photocatalytic and wound healing effects. It should be noted that the modification strategy relies on the “structural foundation” of morphology and size – the physical penetration of needle-shaped nanorods, the sea urchin-like high specific surface area, and the size control of nanoparticles – which directly affect the bacterial contact efficiency, the exposure of active sites, and the external field response ability, thereby determining the antibacterial adaptability. The table below (Table 2) summarizes the morphology, physical properties and synthesis methods of typical Bi₂S₃ nanoreactors, clarifying the structure–performance correlation.

Table 2 The appearance, physical properties and synthesis methods of Bi₂S₃ nanoreactors

Appearance	Physical properties	Synthesis methods	Ref.
Rod-shaped Bi2S3	The band gap is as high as 1.83 eV	Thermal decomposition of sulfur–ligand bismuth complexes	33
Pinetree-like Bi2S3	The surface is about 15.32 m^2 g^−1	Solvothermal synthesis	39
Bi2S3 film	Wide absorption ranging from ultraviolet to infrared wavelengths	CVD	40
Bi2S3 nanoflakes	Broad-spectrum absorption	Liquid phase synthesis	62
Bi2S3 nanospheres	Having a lower negative potential	Solvothermal method	63
Urchin-like Bi2S3 nanospheres	Stable magnetic heat performance	Hard template method	66
Bi2S3 nanorods	Excellent light-to-heat conversion performance	Solvothermal method	73
Urchin-like Bi2S3 hollow microspheres	The specific surface area is 47.06 m^2 g^−1	Hard template method	74
Nanoparticle needle-like Bi2S3	Broad-spectrum absorption	Solvothermal method	76
Bi2S3 hierarchical nanoflower	Excellent charge separation and transport efficiency	Solvothermal method	87
Bi2S3 nanoflowers	Have a lower negative potential	Solvothermal method	92
Bi2S3 nanoparticles	Excellent light-to-heat conversion performance	Solvothermal method	94

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4. Antibacterial mechanism

With the advancement of nanostructure synthesis technology, precisely controlling the morphology, size, and surface properties of such nanostructures to construct multifunctional antibacterial systems become a research hotspot (Fig. 6). However, most existing studies focus on optimizing the synthesis process and testing antibacterial performance, and lack systematic analysis of the structure–activity relationship between their properties and antibacterial mechanisms. This study starts from the structure–activity relationship in nanostructure synthesis and systematically explores the combined antibacterial mechanism of such nanostructures through physical membrane damage, chemical interactions, and immune microenvironment regulation (Table 3). The aim is to reveal the intrinsic relationship between their properties and antibacterial efficacy and then provide theoretical support for designing efficient and low-toxic multi-dimensional antibacterial nanoreactors.

Fig. 6 Schematic diagram of the antibacterial mechanism of Bi₂S₃-based nanoreactors, mainly divided into three categories: physical destruction, chemical interaction, and immune regulation.

Table 3 The antibacterial mechanism of Bi₂S₃-based nanoreactors

Nanoreactors	Bacteria	Antibacterial mechanism	Ref.
Ag–AgCl/Bi2S3	E. coli/S. aureus	Nanoblade effect	61
Ag2S/Bi2S3	E. coli	Nanoblade effect	62
Bi2S3 + GEN	MRSA	Nanoblade effect	63
BiOCl–Bi2S3–Cu2S	E. coli/S. aureus/MRSA	Nanoblade effect	64
Bi2S3@mSiO2@Ag	AmpR E. coli	Nanoblade effect/ion release	65
Fe3O4@Bi2S3	E. coli/MRSA	Nanoblade effect/immune regulation	66
Ru@Bi2S3/Nb2C MXene	E. coli/MRSA	PTT	73
Hollow Bi2S3	E. coli/S. aureus	PTT	74
Bi2S3:Gd@Cu-BIF	E. coli/MRSA	PTT	75
BiOI@Bi2S3/MXene	P. aeruginosa/S. aureus	PTT	76
Cu2Se/Bi2S3	E. coli/S. aureus	PTT	77
Bi2S3@MnO2@Van NRs	S. aureus	PTT	78
Bi2S3−x@PDA	E. coli/S. aureus/MRSA	PDT/immune regulation	84
Defective Bi2S3	E. coli	PDT	55
QBi2S3NPs	E. coli/E. faecalis/B. subtilis	PDT	85
Bi2S3@Ti3C2Tx MXene	E. coli/S. aureus	PDT	86
Bi2S3/CdS	E. coli/S. aureus	PDT	87
MoS2/Bi2S3	E. coli	PDT	88
APs@Bi2S3	E. coli/MRSA	Metabolic interference	91
Ag/Bi2S3	E. coli/S. aureus	Metabolic interference/ion release	92
Ni-doped Bi2S3	S. aureus/B. subtilis/P. aeruginosa	Ion release	53
BSA-Ag@Bi2S3	E. coli/S. aureus/P. aeruginosa	Ion release	93
BSNA	E. coli/S. aureus/P. aeruginosa/MRSA	Immune regulation	94
Zn-CN/P-GO/BiS	MRSA	Immune regulation	27
PG-BiH	E. coli/S. aureus/MRSA	Immune regulation	97
Au@Bi2S3	E. coli/S. aureus	PTT/PDT	98
Rh@BS NFs	E. coli/S. aureus	PTT/PDT	99
VBS-PSA	E. coli/S. aureus	Piezoelectric effect/sonodynamic	100
BiOCl@Bi2S3	E. coli/S. aureus	PTT/PDT/sonodynamic	101

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4.1. Physical damage

Physically destroying the antibacterial mechanism, relying on the precise control of the morphology and size of nanostructures, the nano-scale mechanical stress at the sharp interface is generated by the nanoblade effect, and the bacterial cell membrane is directly punctured and torn. At the same time, the photothermal effect utilizes the light absorption and energy conversion of the material to locally heat up, destroy the bacterial membrane structure, and cause protein denaturation. The two cooperate to achieve antibacterial effects through physical action, providing basic support for the design of antibacterial nanoreactors.

4.1.1. Nanoblade effect destroys the integrity of bacterial membranes. In recent years, nanoblade structures, a novel physical antibacterial strategy, achieved breakthroughs in mechanistic and application research. By tuning nanoscale geometry (such as tip curvature radius, edge sharpness, aspect ratio) to induce specific mechanical interactions with bacterial cell membranes, such structures overcome the drug resistance limitations of traditional chemical sterilization.⁶⁰

The mechanism by which mechanical effects are generated through the regulation of nano-geometric shapes to achieve antibacterial properties was experimentally verified in various composite nanostructures. The following will further explain this in the context of specific examples. For instance, Abdelkader et al. constructed an Ag–AgCl/Bi₂S₃ composite system, which demonstrated a synergistic antibacterial mechanism combining physical effects and photocatalytic effects. In this system, Ag–AgCl NPs ranging from 100 to 700 nm are uniformly loaded on the surface of Bi₂S₃, and the sharp edges formed by these NPs created nanoblade structures that enhanced the antibacterial effect through a dual physical mechanism. The mechanical stress of the nanoblade directly damages the bacterial cell wall, causing the leakage of intracellular substances, then providing a classic paradigm for the design of antibacterial nanoreactors.⁶¹ Similarly, another type of Ag₂S/Bi₂S₃ nanocomposite exhibits a uniform platelet-like and coral-like particle structure with an average particle size of 200–500 nm and a specific surface area as high as 1.0 × 10⁶ m² g⁻¹ (Fig. 7a). This nano-rib-like structure provides abundant active sites for photocatalytic reactions and significantly increases the contact area with bacteria. The sharp nano-rib edges directly damage the bacterial cell membrane through physical cutting actions.⁶² Following this approach, researchers further enhanced the physical cutting ability of the nanoblade by regulating their morphology. Ma et al. innovatively prepared Bi₂S₃ nanospheres with an average particle size of 212 nm. These nanoscale dimensions give them a high specific surface area, significantly increasing the contact area with the bacterial cell membrane. The point contact between the nanospheres and the membrane surface generates high local pressure, causing the membrane lipid molecules to rearrange and destroying the phospholipid bilayer structure of the membrane through mechanical stress, thereby leading to the loss of membrane integrity.⁶³

Fig. 7 (a) The SEM for the Ag/AgCl/Bi₂S₃ composite.⁶¹ Copyright 2024 IOP Publishing. (b) The SEM image of BiOCl–Bi₂S₃–Cu₂S nanosheets.⁶⁴ Copyright 2023 Wiley-VCH GmbH. (c) The TEM image of Fe₃O₄@Bi₂S₃. (d) The corresponding mean fluorescence intensity of 2′,7′-dichlorofluorescin in biofilm after Fe₃O₄@Bi₂S₃ nanocomposite treatment. (e) The biomass of biofilms of MRSA and E. coli under different treatment methods. (f) Relative colony-forming unit (CFU) of MRSA and E. coli biofilms measured by standard plate count after various treatments. (g) The SEM pseudo color images of the biofilm, the yellow spheres represent MRSA, and the purple rods represent E. coli.⁶⁶ Copyright 2024 American Chemical Society.

The ultrathin two-dimensional BiOCl–Bi₂S₃–Cu₂S ternary heterostructure synthesized by Yang et al. fully demonstrates the outstanding application potential of the nano-edge effect in the antibacterial field. This material exhibits the sharp edge characteristics of the ultrathin two-dimensional structure: the atomic-level smooth surface and sharp edges of BiOCl nanosheets, which can damage the bacterial cell membrane through mechanical cutting or piercing (Fig. 7b). In the experiment, the cell membranes of treated E. coli and S. aureus bacteria are significantly damaged and have holes. The Cu₂S and Bi₂S₃ NPs are uniformly distributed on the surface of BiOCl nanosheets. These sharp interfaces further exacerbate the physical damage to the bacteria.⁶⁴

The application of the nanoblade effect also extends to core–shell structures and dynamic response systems. The Bi₂S₃@mSiO₂@Ag nanocomposite prepared by Zu et al. also demonstrates an excellent nanoblade effect. The silver NPs are uniformly distributed on the surface of the mesoporous silica (mSiO₂) shell layer, forming nanostructures with sharp edges or high curvature. These structures directly contact the bacterial cell membrane and utilize the mechanical force at the nanoscale to puncture or cut the cell membrane, resulting in leakage of the cytoplasm and cell death. After treatment with Bi₂S₃@mSiO₂@Ag, various NPs are attached to the surface of E. coli, damage or even completely disintegrate in appearance.⁶⁵ It is worth noting that the Fe₃O₄@Bi₂S₃ nanospheres prepared by Xu et al. have a sea urchin-like sharp edge structure (Fig. 7c). Under the action of a rotating magnetic field (RMF), this structure causes it to rotate in a propeller-like manner, thereby physically disrupting the biological membrane.

After different treatments of the biological membrane, it is observed that the Fe₃O₄@Bi₂S₃ + RMF and Fe₃O₄@Bi₂S₃ + RMF + AMF (alternating magnetic field) treatment groups can significantly disrupt the structure of the biological membrane, resulting in a significant reduction in biomass (Fig. 7d–f). For example, in the study of the biofilms of methicillin-resistant staphylococcus aureus (MRSA) and E. coli, compared with the control group, the SEM pseudo color images of the biofilm show that the membrane structure is severely damaged, and the bacterial quantity is significantly reduced (Fig. 7g), indicating that the sharp structure of the nanospheres can effectively destroy the biological membrane under the magnetic field drive, playing a role similar to a nanoblade, and physically removing the survival barrier of bacteria.⁶⁶

The above cases all confirm the antibacterial effectiveness of the nano-edge structure. These studies consistently show that the antibacterial efficacy of nanoblade structures is closely related to their geometric shape, surface properties, and synergistic mechanism. By carefully designing the structure, the physical destructive power and interface reaction efficiency can be significantly enhanced, providing important theoretical support for the development of new antibacterial nanoreactors.

4.1.2. Photothermal conversion induced membrane phase transition. Photothermal therapy (PTT) is a non-invasive antibacterial technology based on the photothermal effect of nanoreactors. Its core mechanism lies in the utilization of photothermal nanoreactors with NIR absorption properties, which efficiently convert light energy into local heat energy. When the temperature exceeds the phase transition temperature of the bacterial cell membrane, it achieves physical sterilization by disrupting the integrity of the membrane structure. This antibacterial approach based on thermal effects can avoid the problem of traditional antibiotic resistance and has the advantage of penetrating deep tissues.^67,68

The physical state of bacterial cell membranes exhibits significant temperature dependence. At physiological temperature (37 °C), the cell membrane composed of phospholipid bilayers is in a liquid-crystalline phase. At this point, the membrane lipid molecules are loosely arranged, exhibiting good fluidity and substance transport capabilities. When the temperature rises above the phase transition temperature threshold (typically 40–50 °C, depending on the lipid composition of the membrane), a significant phase transition occurs in the membrane system: on the one hand, the intensified thermal motion of membrane lipid molecules leads to disorder in arrangement, forming transient pores or structural cracks; on the other hand, some areas may transform into a gel state, causing a sudden drop in membrane fluidity and the formation of rigid regions. This dual phase transition effect severely disrupts the permeation barrier function and substance exchange ability of the cell membrane, ultimately leading to bacterial death.⁶⁹ The phase transition temperatures of typical pathogenic bacteria vary significantly: E. coli has a relatively high proportion of unsaturated fatty acids in its membrane lipids, and its phase transition temperature is approximately 30 ± 3 °C;⁷⁰ while S. aureus contains a high amount of saturated fatty acids, and its phase transition temperature can reach 43 °C.^71,72 This difference suggests that in the clinical application of PTT, the optical heating parameters (such as irradiation intensity, wavelength, and duration) need to be precisely controlled according to the type of pathogenic bacteria to ensure that the local temperature exceeds the phase transition threshold of the target strain, while avoiding excessive heating that damages the host tissues.

To enhance the light-to-heat conversion efficiency, researchers construct a synergistic system through multi-component composites. Xi et al. designed Ru@Bi₂S₃/Nb₂C MXene nanocomposites based on work function, which exhibit a metal–semiconductor synergy effect: Nb₂C (metallic MXene) absorbs NIR through surface plasmon resonance and converts light energy into heat; Bi₂S₃ exhibits semiconductor properties. It generates heat through carrier relaxation. Meanwhile, the localized surface plasmon resonance effect of ruthenium nanoparticles broadens the light response range to 808 nanometers, thereby enhancing the light absorption efficiency. Under a 1.5 W cm⁻² laser, 300 ppm RBN-1-4 increased the temperature from 24.9 °C to 73.7 °C within 10 min, with a light-to-heat conversion efficiency of 46.6%. The bactericidal rates for E. coli and MRSA were 99.99% and 99.87% respectively.⁷³ Similarly, Bi₂S₃ hollow microspheres in the form of sea urchin-like structures prepared by Wang et al. exhibit excellent photothermal conversion performance (Fig. 8a). Experimental data show that when exposed to an 808 nm, 2.0 W cm⁻² NIR laser at a concentration of 420 µg mL⁻¹ Bi₂S₃ hollow microsphere solution, the temperature can rise to 58.2 °C within 10 min, while DI water only increases by 3.6 °C under the same conditions. Through calculation, the photothermal conversion efficiency is 23.81%, and the thermal transfer time constant τ = 473.53 s. This indicates that the microspheres have excellent light absorption performance and can continuously and stably convert the absorbed NIR energy into heat energy, achieving photothermal killing.⁷⁴

Fig. 8 (a) Schematic diagram of the construction of the TD/Linalool@ composite nanostructure.⁷⁴ Copyright 2019 Elsevier B.V. (b) Photothermal imaging on NIR-irradiated mice sprayed with Bi₂S₃:Gd@Cu-BIF nanocomposite.⁷⁵ Copyright 2022 Acta Materialia Inc. (c) Heating and cooling curves of BiOI@Bi₂S₃/MXene at elevated concentrations under 808 nm NIR (1.5 W cm⁻²) irradiation. (d) The heating and cooling curves of the BiOI, BiOI@Bi₂S₃ and BiOI@Bi₂S₃/MXene under 808 nm irradiation (1.5 W cm⁻²). (e) Temperature variations of BiOI@ Bi₂S₃/MXene across five on/off 808 nm NIR irradiation cycles. (f) Colony counts of P. aeruginosa and S. aureus on BiOI, BiOI@Bi₂S₃, and BiOI Bi₂S₃/MXene after 18-hour cultivation in LB medium. (g) The antibacterial rate of BiOI, BiOI@Bi₂S₃ and BiOI@Bi₂S₃/MXene against P. aeruginosa and S. aureus. (h) Schematic diagram of the PTT/PDT mechanism of BiOI@Bi₂S₃/MXene.⁷⁶ Copyright 2023 Acta Materialia Inc.

The doping of rare earth elements provides a new approach for the design of photothermal nanoreactors. Qi et al. synthesized Bi₂S₃:Gd@Cu-BIF nanocomposites. The Bi₂S₃:Gd NPs in these nanocomposites have strong and broad absorption in the NIR region, enabling them to exhibit excellent photothermal conversion capabilities. When a 100 µg mL⁻¹ solution of the nanocomposite is irradiated by an 808 nm laser with a power density of 1.0 W cm⁻² for 10 min, the temperature increases by approximately 40 °C (Fig. 8b). Through calculation, the photothermal conversion efficiency of this nanocomposite is approximately 52.6%. This highly efficient photothermal conversion performance enables the nanocomposite to generate sufficient heat when exposed to NIR, causing severe damage to bacterial cell walls, cell membranes, and key proteins, thereby achieving the bactericidal effect.⁷⁵

By combining photothermal nanoreactors with two-dimensional nanosheets or core–shell structures, the synergy between thermal effect and photodynamic damage can be further enhanced (Fig. 8h). The BiOI@Bi₂S₃/MXene composite material prepared by Feng et al. has an extremely high photothermal conversion efficiency. At a concentration of 800 µg mL⁻¹, the temperature reaches up to 120.5 °C after 6 min of irradiation (Fig. 8c). After being irradiated with a laser at 808 nm and 1.5 W cm⁻² for 180 s, the core temperature of BiOI@Bi₂S₃/MXene rises sharply from the initial 26.1 °C to 86.1 °C (Fig. 8d). Its photothermal conversion efficiency can reach 57.8%. What is even more astonishing is that during the 5 cycles of opening and closing, the BiOI@Bi₂S₃/MXene nanocomposites maintain a certain level of stability (Fig. 8e).

And in the LB medium, after 18 hours of cultivation, the colony counts and the antibacterial rate of P. aeruginosa and S. aureus on BiOI, BiOI@Bi₂S₃, and BiOI@Bi₂S₃/MXene are measured respectively (Fig. 8f and g). The photothermal conversion efficiency of this composite far exceeds that of common photothermal nanoreactors. Such high photothermal conversion efficiency enables the nanocomposites to rapidly convert light energy into heat energy under illumination, and this eventually serves to achieve a sterilization effect.⁷⁶

In addition to the aforementioned Bi₂S₃-based composite systems constructed through rare earth doping or combined with two-dimensional nanosheets and core–shell structures, other multicomponent structures based on Bi₂S₃ also demonstrate excellent performance in the field of photothermal antibacterial, providing more ideas for the design and application of photothermal nanoreactors. Correspondingly, Yu et al. prepared Cu₂Se/Bi₂S₃. The absorption edge of the Cu₂Se/Bi₂S₃ nanocomposite exceeded 1000 nm, demonstrating excellent NIR absorption capability and the potential to convert NIR into thermal energy. Calculations showed that the photothermal conversion efficiency of this composite was as high as 37.23%. When tested at different concentrations, as the concentration of the Cu₂Se/Bi₂S₃ nanocomposite increased, the corresponding solution temperature also increases. At the same time, this nanocomposite also has excellent photothermal stability. The excellent photothermal conversion ability of Cu₂Se/Bi₂S₃ increases the permeability of bacterial cell membranes, thereby destroying the structure and function of bacteria and achieving the antibacterial purposes.⁷⁷ The Bi₂S₃@MnO₂@Van NRs prepared by Li et al. exhibit excellent photothermal effects when exposed to 808 nm laser irradiation. When the concentration of Bi₂S₃@MnO₂@Van NRs reaches 200 µg mL⁻¹, after 10 min of 808 nm laser (1.0 W cm⁻²) irradiation, the solution temperature can increase from 37.7 °C to 52.8 °C. The bacterial inactivation efficiency is further evaluated using the plate counting method, and statistical analysis shows that the antibacterial rate is as high as 99.10%, proving that Bi₂S₃@MnO₂@Van NRs as a photothermal agent have a rapid lethal bactericidal efficiency.⁷⁸

The membrane phase transition induced by photothermal conversion can avoid antibiotic resistance by disrupting the fluidity and integrity of the cell membrane, combined with oxidative stress and heat shock responses. Moreover, NIR can penetrate deep tissues and can achieve efficient antibacterial effects. This mechanism is universal and applicable to Gram-positive/Gram-negative bacteria and drug-resistant strains, providing a theoretical basis for the development of new antibacterial strategies. While photothermal antibacterial technology has become an important direction for combating bacterial infections due to advantages such as non-induction of drug resistance and broad-spectrum activity, it is constrained by inherent limitations. Specifically, photothermal antibacterial technology relies on external light irradiation of specific wavelengths to stimulate heat generation; however, this light has limited penetration depth in biological tissues, making it difficult to act on deep organ infections. Additionally, the relatively high temperatures required for antibacterial effects may damage normal cells – these factors collectively restrict the application of this technology.

4.2. Chemical interactions

The antibacterial mechanism of chemical interactions encompasses various patterns that destroy the physiological functions of bacteria through chemical reactions, substance transformation, or charge interactions. The main ones include: photodynamic ROS antibacterial, which utilizes photosensitizers to produce ROS such as ˙OH and ¹O₂ under light excitation, causing damage by oxidizing bacterial membrane lipids, proteins, and DNA; sulfide interference with metabolism antibacterial, which utilizes the semiconductor properties or ionic interactions of sulfides (such as Bi₂S₃) to interfere with the bacterial electron transfer chain, enzyme activity, or metabolic pathways, inhibiting their proliferation; ionic release antibacterial, which releases metal ions such as Bi³⁺, Ag⁺, etc., or H⁺, to disrupt the bacterial cell membrane potential, chelate essential metal ions or change the microenvironment pH, achieving a bactericidal effect. These three mechanisms all achieve antibacterial effects through specific interactions between chemical substances and bacteria, targeting the destruction of their structure or metabolic balance.

4.2.1. Photodynamic antibacterial effects. Photodynamic therapy (PDT), as an emerging antibacterial strategy, has received considerable attention in recent years. It utilizes the interaction between photosensitizers, light, and oxygen to kill bacteria, and has many advantages, such as broad-spectrum antibacterial activity, low susceptibility to drug resistance, and good temporal and spatial controllability. Its antibacterial mechanism mainly relies on the generation and action of ROS. The photosensitizer is excited under specific wavelength light and transitions from the ground state to the excited state. The excited photosensitizer mainly produces ROS through two reaction pathways to kill bacteria:

(1) Type I reaction: the excited photosensitizer directly undergoes electron transfer with surrounding biomolecules, generating ˙O₂⁻, ˙OH, etc. These free radicals exhibit extremely high chemical reactivity. For example, the oxidation potential of the hydroxyl radical is 2.8 V, which can non-specifically oxidize bacterial cell membranes, proteins, and nucleic acids, and damage the cell structure and function.

(2) Type II reaction: the excited photosensitizer transfers energy to molecular oxygen, converting the ground-state triplet oxygen into singlet oxygen (¹O₂). Singlet oxygen is also a strong oxidant with an oxidation potential of 1.7 V, which can oxidize the unsaturated fatty acids of the bacterial cell membrane to trigger lipid peroxidation, damaging membrane integrity; it can also oxidize protein amino acid residues and react with nucleic acid bases, affecting the transmission and replication of bacterial genetic information.

The ROS generated by photodynamic therapy has extremely strong oxidizing properties. They can undergo peroxidation reactions with the lipid components in the bacterial cell membrane. Taking E. coli as an example, the abundant phospholipid bilayer in the cell membrane is easily attacked by ROS.⁷⁹ Under photodynamic treatment, the ROS cause the fatty acid chains of the E. coli cell membrane to undergo peroxidation, thereby changing the fluidity and permeability of the cell membrane. Data from Johnson et al. show that after photodynamic antibacterial treatment, through membrane potential detection and fluorescence labeling tracing and other technical means, it can be observed that the cell membrane potential of E. coli significantly decreases, and some small molecules that could not pass through the cell membrane can enter the cell, indicating an increase in cell membrane permeability. The destruction of the cell membrane structure and function will lead to the leakage of cell contents, thereby causing bacterial metabolic disorders, and ultimately resulting in bacterial death.⁸⁰ ROS also can cause oxidative damage to biological macromolecules such as nucleic acids and proteins within bacterial cells. In terms of nucleic acid damage, Fleming et al. found in their 2024 study that ˙OH in ROS can cause oxidative radicals (DNA bases). For example, ˙OH can oxidize guanine to 8-hydroxyguanine, and this modified product will affect the normal replication and transcription processes of DNA.⁸¹

In terms of proteins, reactive oxygen can oxidize amino acid residues in proteins, such as the sulfhydryl group of cysteine and the thioether group of methionine, which are easily oxidized. These damages to biological macromolecules will interfere with the normal physiological and biochemical reactions within bacterial cells, ultimately leading to bacterial death.⁸² Moreover, many bacteria form biofilms during infection, which provide a protective barrier for bacteria and increase the difficulty of antibacterial treatment. ROS can oxidize extracellular polymers (EPS) in biofilms, such as polysaccharides and proteins. Photodynamic treatment causes a significant reduction in EPS content, making the structure of the biofilm loose and the interconnection between bacteria is weakened. At the same time, reactive oxygen can regulate the expression of genes related to biofilms, inhibit the formation of bacterial biofilms, and enhance the killing effect on bacteria.⁸³

To enhance photocatalytic activity, researchers optimize the charge separation efficiency through sulfur vacancy engineering and heterostructure construction. For instance, Mo et al. synthesized the Bi₂S_3−x@PDA heterojunction, which consists of Bi₂S₃ nanorods rich in sulfur vacancies and a PDA shell. This structure enhances photocatalytic activity by improving the transfer of photogenerated charges and the separation of electrons and holes (Fig. 9a). After NIR irradiation, the absorbance of the Bi₂S_3−x@PDA group at 530 nm increases significantly, effectively generating ROS (Fig. 9b and c). In in vitro antibacterial experiments, using Gram-positive S. aureus, Gram-negative E. coli, and methicillin-resistant S. aureus as model bacteria, through plate coating and optical density (OD) detection, it is found that under NIR irradiation, the antibacterial rate of the Bi₂S_3−x@PDA treatment group is significantly increased, with the Bi₂S_3−x@PDA + H₂O₂ treatment group having the best antibacterial effect.⁸⁴ Sun et al.'s research synthesized Bi₂S₃ nanorods containing different types of element vacancies by solvothermal method and studied their NIR-driven photocatalytic bactericidal activity, revealing the influence of element vacancies on ROS generation. During the photocatalytic process, the photogenerated electrons and holes would react with surrounding substances to generate ROS. In photocatalytic inactivation experiments, the Bi₂S_3−x sample with bismuth vacancies could completely inactivate approximately 7 log of E. coli within 40 min of NIR irradiation. The morphology of untreated E. coli is intact, while after photocatalytic inactivation, the intact morphology of the bacteria is severely damaged, with collapsed and damaged pore diameters, which prove the damage caused by the ROS produced by Bi₂S₃ nanorods toward the bacteria. This finding confirmed that vacancy engineering not only regulates charge separation but also directs the directional generation of specific ROS species through energy level matching, providing a possibility for precise antibacterial effects.⁵⁵

Fig. 9 (a) A schematic diagram illustrating the generation of ROS by Bi₂S_3−x@PDA NPs under NIR irradiation. (b) Nitro blue tetrazolium absorption spectra for detecting ˙O₂⁻ generation under NIR irradiation with Bi₂S_3−x, PDA, or Bi₂S_3−x@PDA (with/without H₂O₂). (c) MB solution degradation curves for detecting ˙OH generation in different samples under NIR light irradiation.⁸⁴ Copyright 2024 Wiley-VCH GmbH. (d) ROS production experiment with a DCFH fluorescent probe (200 ppm) showing mean ± standard deviation from a representative experiment (n = 3 independent samples). (e) Photocurrent response under 808 nm NIR irradiation.⁸⁶ Copyright 2025 Springer Nature. (f) Under light and dark conditions, electron paramagnetic resonance spectra of DMPO-˙O₂⁻ and DMPO-˙OH by BC-DMF under light irradiation and dark conditions.⁸⁷ Copyright 2021 Elsevier B.V. (g) The photodynamic antibacterial mechanism.⁹³ Copyright 2022 Elsevier B.V.

Combining ROS generation with functional molecules can further optimize the antibacterial performance. Verma et al. synthesized Quercetin-supported Bi₂S₃ NPs, which also exhibited significant photodynamic antibacterial activity. When excited by visible light, the electrons and holes are generated, reacting with water and oxygen to produce ROS (such as ˙OH and ˙O₂⁻), which cause oxidative stress and damage the bacterial structure. In antibacterial experiments, the antibacterial activity of QBi₂S₃NPs against coli, E. faecalis, and Bacillus subtilis is determined using the agar diffusion method. The results show that the diameters of the inhibition zones are 20 ± 2 mm, 18 ± 1 mm, and 15 ± 1 mm, respectively, clearly indicating that QBi₂S₃NPs have inhibitory effects on the growth of these bacteria. At the same time, the MIC values of QBi₂S₃NPs against E. coli, E. faecalis, and B. subtilis are 20 ± 2 µg mL⁻¹, 30 ± 3 µg mL⁻¹, and 40 ± 3 µg mL⁻¹, respectively, compared to pure quercetin, which fully demonstrate that QBi₂S₃NPs have stronger antibacterial ability.⁸⁵ Based on Schottky junctions and heterojunctions, researchers constructed multi-component ROS efficient generation systems. For example, Li et al. constructed Bi₂S₃@Ti₃C₂T_x MXenes, based on different work functions, and when Ti₃C₂T_x and Bi₂S₃ come into contact, a Schottky junction is formed. Under 808 nm NIR irradiation, the Schottky barrier effectively inhibits electron reflow, greatly promoting the separation of electron–hole pairs, significantly increasing the concentration of free carriers (Fig. 9e). These photogenerated charges quickly transfer to surrounding species, thereby generating a large amount of highly oxidizing ROS, which can damage bacterial cell walls, cell membranes, proteins, nucleic acids and other biological macromolecules, achieving efficient antibacterial effects (Fig. 9d).⁸⁶

In addition to optimizing the antibacterial performance by regulating ROS generation through functional molecule loading and Schottky junctions, the heterojunction systems designed based on different energy level structures also provide a new direction for efficient ROS-mediated antibacterial strategies. Correspondingly, Shi et al. synthesized a hierarchical Z-scheme Bi₂S₃/CdS heterojunction, in which Bi₂S₃ and CdS have different Fermi levels. The two nanocomposites form a Z-type heterojunction. The Bi₂S₃/CdS nanostructures synthesized in ethylene glycol (BC-EG) and N,N-dimethylformamide (BC-DMF) are assembled by Bi₂S₃ nanowires and CdS NPs. To further investigate the generation mechanism of reactive ROS produced by BC-DMF, we used 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as an optical agent to capture ˙O₂⁻ under both light and dark conditions (Fig. 9f). Clearly, the electron–hole recombination spectrum indicates that ˙OH is not generated. Using E. coli and S. aureus as experimental strains, the antibacterial performance of the photocatalyst was evaluated by the plate counting method. When illuminated for 60 minutes, the antibacterial efficiencies of BC-DMF and BC-EG against E. coli reached 100.00% and 87.50%, and respectively. This data fully demonstrates that the Bi₂S₃/CdS heterojunction has excellent antibacterial performance.⁸⁷ Furthermore, Pasdar et al. synthesized a MoS₂/Bi₂S₃ heterostructure with an energy band gap of 1.79 eV. This smaller band gap enables it to have higher photocatalytic activity in the visible light and NIR regions. Through antibacterial experiments, using E. coli as the test strain, sterilize discs loaded with Bi₂S₃, MoS₂, and MoS₂/Bi₂S₃ particles are placed on NA agar plates containing E. coli, and culture under NIR irradiation and without light conditions respectively. The results show that under NIR irradiation, the diameters of the antibacterial zones of Bi₂S₃, MoS₂, and MoS₂/Bi₂S₃ particles against E. coli are 2.6 mm, 3.2 mm, and 6.1 mm respectively. The diameter of the antibacterial zone of MoS₂/Bi₂S₃ particles under NIR irradiation was the largest, indicating the strongest antibacterial performance, which is attributed to the higher ROS production ability of this heterostructure.⁸⁸

Photodynamic therapy relies on photosensitizers, light, and oxygen to exhibit antibacterial power. The ROS generated by type I and type II reactions damage bacteria from multiple aspects such as cell membranes, nucleic acids, proteins, and biological membranes, disturbing their metabolism and genetics, and causing the disintegration of the biological membrane, leading to bacterial death (Fig. 9g). From sulfur vacancy regulation to heterojunction band engineering design, the ROS antibacterial effect of photodynamic therapy is rapidly advancing along the path of “mechanism analysis–innovation of nano-reactors–application expansion”. Through the verification of various Bi₂S₃ composite systems, when the photogenerated charge separation efficiency of the nano-composite materials reaches the critical value, their ability to destroy drug-resistant bacteria and biofilms will achieve a qualitative leap, providing a highly potential new strategy for addressing the antibiotic resistance crisis.

4.2.2. Sulfides interfere with metabolism to exert antibacterial effects. Sulfides act as electron donors or interference factors in the bacterial respiratory chain, influencing energy metabolism through redox reactions. Their redox pairs give them the ability to conduct electron transfer, but high concentrations of sulfides can bind to key enzymes of the respiratory chain, inhibiting the efficiency of electron transfer. For instance, in E. coli, high concentrations of sulfides feedback inhibit ATP sulfatase (encoded by cysD/N) and APS kinase (CysC), hindering sulfate reduction, indirectly interfering with the electron transfer of the respiratory chain, and further exacerbating energy metabolism disorders.⁸⁹

The metabolism of sulfides is closely linked to the respiratory chain and is also interrelated and interdependent with other metabolic pathways.⁹⁰ In E. coli, when sulfide supply is insufficient, it will affect the synthesis of methionine, leading to a reduction in S-adenosylmethionine (AdoMet) synthesis, affecting the methylation modification of respiratory chain-related proteins, and thereby interfering with the normal function of the respiratory chain. This demonstrates the mechanism by which sulfide metabolism indirectly exerts an important influence on the respiratory chain through its effects on other metabolic pathways. In addition to blocking the respiratory chain, sulfides also kill bacteria through dual pathways of enzyme activity inhibition and oxidative stress. Sulfides can inhibit key metabolic enzymes by binding to the active site of enzymes or altering their conformation. In the methionine cycle, insufficient sulfide supply will reduce the synthesis of AdoMet, affecting the methylation modification of respiratory chain-related proteins (such as ATP synthase subunits), and thereby interfering with the function of electron transfer chain proteins. Furthermore, sulfides can induce the generation of ROS or interfere with the antioxidant system, disrupting the redox homeostasis within the cell.

Bi₂S₃, as an excellent antibacterial property among sulfides, is a narrow-bandgap semiconductor. When excited by NIR (808 nm), it generates photogenerated electrons and holes. Among them, e⁻ can efficiently oxidize and reduce nicotinamide adenine dinucleotide (NADH) to NAD⁺, disrupting the NADH/NAD⁺ homeostasis within bacteria. NADH is a key coenzyme in bacterial energy metabolism (such as in the tricarboxylic acid cycle and electron transport chain), and its homeostasis imbalance can lead to a blockage in energy synthesis and prevent bacteria from maintaining normal physiological activities. Additionally, the electrons generated by NIR excitation of Bi₂S₃ can react with oxygen to form ˙O₂⁻, triggering ROS bursts and damaging bacterial DNA, proteins, and cell membranes. The accumulation of ROS further inhibits NADH-related enzyme activities, while the oxidation of NADH to NAD⁺ exacerbates oxidative stress, forming metabolic-oxidative dual damage. Vitro experiments show that after treatment with APs@Bi₂S₃ and NIR, the survival rate of resistant bacteria drops below 1%, and the cell membranes are severely damaged. In the mouse model of resistant bacteria infection wound, this spray significantly promotes wound healing, with the wound almost closing by the 9th day, and the bacterial colony count is reduced to 0–2 orders of magnitude. Thus, sulfur-containing Bi₂S₃ achieves dual metabolic-physical killing of resistant bacteria through photocatalytic NADH oxidation and ROS generation, combines with the membrane-damaging effect of the peptide body, and provides a new strategy for antibiotic-resistant infections.⁹¹ In the hierarchical 3D Ag/Bi₂S₃ nanoflower system synthesized by Jia et al., the lactate dehydrogenase (LDH) activity measurement shows that 1000 µg mL⁻¹ of Ag/Bi₂S₃ can reduce the LDH activity of E. coli and S. aureus by 41.5% and 31.8%, respectively. As a key respiratory enzyme bound to the cell membrane, when it loses its activity it directly blocks bacterial energy metabolism.⁹²

The advantage of sulfides interfering with metabolic antibacterials lies in their inhibition of the source of energy metabolism, and nanoreactors such as Bi₂S₃ can achieve spatially and temporally controllable metabolic intervention through photocatalysis. From respiratory chain blockade to NADH homeostasis regulation, sulfides as antibacterial agents are providing a unique “metabolic network targeting” advantage for combating resistant bacteria, different from traditional antibiotics. As shown in the research of AgBi₂S₃ nanoflowers and APs@Bi₂S₃, when the nanocomposites design is deeply combined with the metabolic mechanism, the efficiency of destroying bacterial energy metabolism will be significantly improved, opening technical routes for the treatment of infectious diseases.

4.2.3. Ion release antimicrobial properties. The ionic release-based antibacterial strategy, as a novel technology based on the inherent antibacterial activity of metal ions, achieves efficient and broad-spectrum antibacterial effects by releasing metal ions with bactericidal properties. These ions disrupt the cell membrane structure of microorganisms, interfere with their metabolic processes and genetic substance synthesis. This mechanism not only avoids the toxic side effects of traditional organic antibacterial agents but also enables long-lasting antibacterial performance by regulating the release rate of ions, providing important theoretical basis and technical support for antibacterial design in medical substance, public health, and environmental management fields. Bi₂S₃-based nanocomposites constructed by introducing metal ions (such as Ag⁺, Ni²⁺) can achieve efficient antibacterial effects through the synergistic effect of ion release and structure.

The Bi₂S₃-based composites achieve antibacterial effects through the release of metal ions and structural synergy, and the mesoporous carrier is particularly crucial for optimizing the ion release kinetics. In the Bi₂S₃@mSiO₂@Ag nanocomposite prepared by Zu et al., the mesoporous silica (mSiO₂) acts as a carrier and can uniformly disperse Ag NPs, delaying the release rate of Ag⁺, achieving long-term antibacterial effects in vivo, reducing agglomeration and regulating the release kinetics of Ag⁺. In vivo experiments confirm that oral administration of Bi₂S₃@mSiO₂@Ag reduces the bacterial count in the intestinal tract of infected mice by 3 orders of magnitude (colon) and 2 orders of magnitude (blind colon, small intestine), demonstrating the optimization effect of the mesoporous carrier on the release of Ag⁺ in the in vivo environment. Long-term toxicity experiments show that after oral administration of Bi₂S₃@mSiO₂@Ag (10 mg mL⁻¹) for 30 days, there were no abnormalities in the weight, blood biochemical indicators, and histological structures of major organs (heart, liver, kidney, etc.) of the mice, which also confirmed its good biocompatibility.⁶⁵

Improving the contact efficiency between ions and bacteria is the key path to enhancing antibacterial efficacy. In the hierarchical 3D Ag/Bi₂S₃ nanoflowers system synthesized by Jia et al., the layered structure provides a high specific surface area, allowing the Ag⁺ release sites to be uniformly distributed and enhancing the contact efficiency with bacteria. The release of Ag⁺ directly leads to the disruption of bacterial cell membrane integrity. Experimental data show that when the concentration of Ag/Bi₂S₃ is 500 µg mL⁻¹, the intracellular protein leakage concentrations of E. coli and S. aureus reach 18.2 µg mL⁻¹ and 14.0 µg mL⁻¹, respectively, significantly higher than 8.5 µg mL⁻¹ and 3.6 µg mL⁻¹ at 125 µg mL⁻¹ (concentration-dependent). Through 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) probe detection, it was found that 500 µg mL⁻¹ of Ag/Bi₂S₃ can increase the intracellular ROS levels of E. coli and S. aureus by 4.0 times and 3.1 times, respectively. This indicates that the ROS generation induced by Ag⁺ release breaks the bacterial antioxidant balance, leading to oxidative damage to biological macromolecules such as DNA and proteins.⁹²

By doping metal ions to change the lattice structure of Bi₂S₃, it can thermodynamically promote ion release and antibacterial activity. In the Ni-doped Bi₂S₃ nanocomposites prepared by the reverse micelle method by Darji et al., Ni²⁺ (ion radius 69 pm) replaces Bi³⁺ (117 pm), resulting in significant changes in lattice parameters. This structural distortion increases the density of surface defects, providing a thermodynamic driving force for the release of Ni²⁺. Experiments show that the MIC of pure Bi₂S₃ for S. aureus and B. subtilis is 60 µg mL⁻¹ and 70 µg mL⁻¹, respectively, while the MIC after 2.0 wt% Ni doping drops to 55 µg mL⁻¹ and 60 µg mL⁻¹; for Gram-negative bacteria S. marcescens and P. aeruginosa, the MIC decreases from 70 µg mL⁻¹ to 60 µg mL⁻¹. This discovery reveals that ion doping not only directly kills bacteria by releasing metal ions but also enhances the oxidative stress response through optimizing semiconductor properties. Additionally, by regulating ion release using natural protein carriers, the cytotoxicity can be reduced while maintaining antibacterial activity. Bovine serum albumin serves as a natural protein carrier, binding to Ag⁺ and Bi³⁺ through functional groups such as amino and carboxyl groups to form stable complexes. This process not only reduces the aggregation of Ag NPs but also lowers cytotoxicity through a sustained-release mechanism (such as a survival rate of >90% for LO₂ cells at 100 µg mL⁻¹), while maintaining antibacterial activity.⁵³ In Ayodhya's research, Ag@Bi₂S₃ composites are synthesized through BSA-mediated synthesis, and their antibacterial mechanisms were systematically studied. The Ag NPs in Ag@Bi₂S₃ release Ag⁺ that can penetrate the bacterial cell membrane and disrupt its integrity. In the experiment, the inhibition zone diameters of Ag@Bi₂S₃ against bacterial strains such as E. coli and S. aureus reached 15.34 mm and 16.81 mm, respectively. This indicates that the interaction between the released Ag⁺ and the bacterial cell membrane is the key step in antibacterial activity, and it causes membrane disorder and content leakage by binding to membrane proteins with sulfhydryl (–SH) groups. In the experiment, Ag@Bi₂S₃ achieve a degradation efficiency of 98.38% for mixed dyes under sunlight, and the generated active species (such as ˙O₂⁻) can synergize with Ag⁺ to exert antibacterial effects.⁹³

All the above studies indicate that Bi₂S₃-based nanocomposites achieve efficient antibacterial effects through the multiple mechanisms of “ion release–structure synergy–oxidative stress”. Whether it is the sustained-release design of mesoporous carriers, the optimization of three-dimensional structure contact, or the lattice regulation of ion doping, or the reduction of toxicity by protein carriers, all point to the core goal of “antibacterial efficiency–biological safety”. When the nanoreactors’ structure design is deeply coupled with the ion release kinetics, its ability to balance antibacterial efficiency and biological compatibility will achieve a qualitative improvement, promoting the development of antibacterial nanoreactors towards precise treatment.

4.3. Immune regulation

Bacterial infections pose a persistent threat to human health, but traditional antibiotic treatments are increasingly compromised by growing bacterial resistance, with many once-effective antibiotics losing efficacy. This renders sole reliance on antibiotics inadequate for clinical anti-infection therapy. As a novel strategy, immunomodulatory antibacterial therapy offers a new direction: by regulating immune function to enhance the body's immune response against bacteria, it enables more effective bacterial recognition and elimination. Unlike direct bacterial killing, this approach stimulates the body's own defenses, addressing infection root causes while avoiding antibiotic resistance—providing a fresh perspective for treating resistant bacterial infections.

This strategy of enhancing antibacterial effects by regulating the function of the immune system is verified in the design and application of specific nanoreactors. Taking functionalized nanoreactors as an example, next we will specifically explain how they achieve efficient antibacterial effects through the immune regulation mechanism. For example, Li et al. prepared functionalized nano-bisulfide selenide (BSNA), which exhibits a unique immune regulatory antibacterial mechanism, effectively enhancing the antibacterial effect and reducing the inflammatory response. This nanocomposite can stimulate the production of more CD8⁺ T cells. As key effector cells in the immune system, CD8⁺ T cells can directly kill bacteria-infected cells, thus effectively controlling infection spread. By recruiting CD8⁺ T cells, BSNA inhibits the expression of inflammatory factors, thereby reducing inflammation. By downregulating the expression of xerC/xerD, it reduces the bacterial uptake and utilization of glucose, leading to the inhibition of bacterial growth. On the other hand, BSNA can disrupt the secondary structure of heat shock proteins HSP70/HSP90, preventing them from functioning normally to protect the bacteria from external stimuli. By nitro sating TYR179, BSNA alters the structure of HSP70, affecting the intramolecular hydrogen bonds, thereby reducing the activity of HSP70 and making the bacteria more sensitive to environmental stress, enhancing the antibacterial effect.⁹⁴

In addition, Huang et al. constructed a dual elemental doping activated signaling pathway of angiogenesis and defective heterojunction, which can promote angiogenesis. Through proteomics analysis, it is found that Zn-CN/P-GO/BiS can upregulate the expression of angiogenesis-related proteins in the hypoxia-inducible factor-1 (HIF-1) signaling pathway, thereby promoting angiogenesis. In the KEGG pathway enrichment analysis, after treatment with this nanocomposite, the HIF-1 signaling pathway is significantly enriched, and the expression of related proteins in the pathway is upregulated. These nanoreactors provide necessary nutrients and oxygen supply for wound healing, enhancing the local tissue's anti-infection ability. At the same time, Zn-CN/P-GO/BiS can also upregulate various proteins related to adipocyte differentiation, lipid metabolism, and inflammatory responses in the peroxisome proliferator-activated receptor signaling pathway.

The PPAR signaling pathway plays an important role in maintaining metabolic homeostasis, regulating lipid metabolism, and inflammatory responses. In in vivo experiments, through the study of infected wounds, it is found that the treatment group with Zn-CN/P-GO/BiS returns the levels of white blood cells (WBCs) and granulocytes to normal after 12 days of treatment. WBCs and granulocytes are typical inflammatory markers, and their normalization indicates that Zn-CN/P-GO/BiS has significant antibacterial activity in vivo, can effectively alleviate inflammatory responses, regulate immune cell functions, and promote wound healing.²⁷

Macrophages are a type of highly heterogeneous immune cell with strong plasticity. They can polarize into different functional phenotypes based on the signal stimulation of the microenvironment and play a key role in immune responses, tissue repair, and inflammatory reactions during physiological and pathological processes. Based on the activation state and functional characteristics, macrophage polarization mainly includes classical activated M1 type and selective activated M2 type. In the T helper 1 cell (Th1) immune response and in the context of acute inflammation. M1 type macrophages can be activated by stimulants such as IFN-γ and LPS. After activation, there will be significant changes in gene expression, which will subsequently lead to the release of a large amount of pro-inflammatory cytokines, such as those mentioned by Murray et al. M1 type macrophages exhibit strong antibacterial and anti-tumor properties. In terms of antibacterial action, they can release a large amount of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, etc., to initiate the immune response and limit the growth and spread of bacteria.⁹⁵ The M2 type macrophages play a significant role in T helper 2 cell (Th2) -type immune responses and tissue repair processes. They mainly produced Th2 cytokines such as IL-4 and IL-13. The M2 type macrophages are involved in immune regulation and tissue reconstruction processes, and can release anti-inflammatory cytokine IL-10, inhibit excessive inflammatory responses and reduce tissue damage.⁹⁶ For instance, Abbaszadeh et al. prepared a PG-BiH hydrogel. In this hydrogel, the CCM served as a multiantigen agent, working in synergy with PTT to exert immunomodulatory effects. After PTT treatment of cancer cells, the cells release substances such as tumor-specific antigens, heat shock proteins, and cell debris. These substances could activate immune effector cells and promote the maturation of dendritic cells (DCs). The mature DCs would migrate to the lymph nodes and present tumor antigens to T cells, activating the T-cell-mediated immune response, thereby triggering systemic anti-tumor immunity (Fig. 10f).⁹⁷

Fig. 10 (a) Illustration of treating MRSA biofilm-infected wounds using Bi₂S_3−x@PDA HJs. (b) Schematic diagram illustrating antioxidant stress-induced ROS clearance for anti-inflammatory effects and potential mechanism of macrophage reprogramming. (c) Flow cytometry analysis of M1 macrophage-specific marker CD86 and M2 macrophage-specific marker CD206 under different experimental treatments.⁸⁴ Copyright 2024 Wiley-VCH GmbH. (d) Collective analysis of immune system-related genes (GSEA) with markers below the curve representing each gene's ranking and normalized enrichment score (NES) as the standard enrichment score. (e) Important KEGG enrichment functions in macrophages – gene interaction network with square nodes for functional information, circular nodes for genes, and lines for gene-function associations.⁶⁶ Copyright 2024 American Chemical Society. (f) Immunotherapy: Through cancer cell membranes (CCM), tumor-associated antigens are delivered to antigen-presenting cells.⁹⁷ Copyright 2025 Elsevier B.V.

The phenotypic transformation of macrophages plays a central role in immune regulation and infection response, and nanoreactors can precisely control this process through specific structural design. For example, Mo et al. synthesized sulfur vacancy-rich Bi₂S_3−x@PDA heterojunctions and conducted experiments to test macrophages. They induced macrophages using lipopolysaccharide (LPS) and analyzed surface biomarkers (M1 type: CD86; M2 type: CD206) using flow cytometry to evaluate the macrophage phenotype (Fig. 10c). The results show that macrophages treated with PDA and Bi₂S_3−x@PDA HJs have weak CD86 expression and strong CD206 expression. At the same time, through RT-qPCR detection, it is found that the genes encoding representative M1-type biomarkers such as inducible nitric oxide synthase and Toll-like receptor-4 (TLR-4) are significantly upregulated in the LPS-treated group, while the expression of representative M-type biomarkers such as CD163 and arginase-1 (Arg-1) do not change apparently (Fig. 10d). This clearly indicates that Bi₂S_3−x@PDA HJs can drive macrophages to transform from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype (Fig. 10b). In in vivo experiments, a mouse wound model with MRSA biofilm infection is constructed, and the macrophage population at the wound site is studied. The results show that in the wounds treated with Bi₂S_3−x@PDA HJs, the percentage of M1 macrophages (CD68+/CD86+) is significantly lower than in other treatment groups. This further confirms that Bi₂S_3−x@PDA HJs can promote the transformation of macrophages from the M1 phenotype to the M2 phenotype in vivo, inhibit inflammatory responses, support tissue remodeling, and play a key role in the immune regulation and antibacterial process (Fig. 10a).⁸⁴ Furthermore, Xu et al. innovatively utilized the sea urchin-shaped Fe₃O₄@Bi₂S₃ nanospheres to regulate the immune response to combat infections. On one hand, the sea urchin-like structure of the nanospheres and the generated ROS can stimulate macrophages to polarize into the M1 phenotype. Through flow cytometry, immunofluorescence staining, and western blot analysis, it is clear that after treatment with Fe₃O₄@Bi₂S₃ the expression of M1 marker CD80 in RAW264.7 macrophages significantly increased, while the expression of M2 marker CD206 decreased relatively. On the other hand, the study of the immune signal changes in RAW264.7 macrophages through RNA sequencing reveal that after Fe₃O₄@Bi₂S₃ treatment, immune-related signaling pathways such as the TNF signaling pathway, chemokine signaling pathway, and NF-κB signaling pathway are activated. At the same time, the gene interaction network diagram highlights the cytokine–cytokine receptor interactions and the TNF signaling pathway as the key pathways for macrophage activation in immunosuppressive biofilms (Fig. 10d). The RT-qPCR results also show that the expression of genes such as TNF-α, IL-1β, and IL-6 significantly increases in the Fe₃O₄@Bi₂S₃ + RMF and Fe₃O₄@Bi₂S₃ + RMF + AMF treatment groups, while the expression of IL-10 slightly decreases, indicating that these signaling pathways are in an activated state (Fig. 10e). Activated M1-type macrophages can clear metabolically inactive bacteria through phagocytosis, enhance the body's resistance to infection, promote the recovery of implantation site infection, and inhibit infection recurrence.⁶⁶

The field of immunomodulatory antibacterial therapy is currently in a period of vigorous development. The numerous research results demonstrate broader application prospects. From the stimulation of CD8⁺ T cells by nano-Bi₂S₃ to the regulation of macrophage polarization, these innovative achievements are constantly expanding the boundaries of immunomodulatory antibacterial therapy. However, the molecular mechanisms in basic research have not yet been fully elucidated, and there are still issues such as safety and cost during the clinical translation process. Looking to the future, with the deep integration of multiple disciplines, such as collaborative innovation in fields like materials science, immunology, and medical engineering, these challenges are expected to be overcome. This will bring new hope to anti-infection treatment and offer a new dawn for the cause of human health.

The above three primary antibacterial methods operate through distinct yet complementary mechanisms: physical damage leverages the nanoblade effect (Fig. 11a), where sharp nanostructures generate mechanical stress to rupture bacterial membranes; and the photothermal effect, which converts light energy into local heat to disrupt membrane integrity and denature proteins; chemical interactions encompass photodynamic reactions that produce reactive oxygen species to oxidize bacterial components, sulfide-mediated interference with metabolic pathways, and ion release (such as Ag⁺) that damages membranes and induces oxidative stress (Fig. 11b); immune regulation enhances the host's intrinsic defenses by stimulating immune cells like CD8⁺ T cells and macrophages, regulating macrophage polarization, and activating signaling pathways to promote bacterial clearance and tissue repair (Fig. 11c).

Fig. 11 (a) Schematic diagram of Bi₂S₃ nanoblades physically damaging bacterial cell membranes and causing bacterial death. (b) Illustration of Bi₂S₃-based nanoreactors producing ROS in bacteria, disrupting cell structure and causing cell death. (c) Schematic diagram of Bi₂S₃-based nanoreactors stimulating the body's immune system to attack bacteria and cause their death.

4.4. Combined antibacterial effects

Although a single Bi₂S₃ exhibits excellent antibacterial performance due to its own semiconductor properties, photothermal effects, and low drug resistance induction, its antibacterial efficacy still has room for improvement when dealing with clinical challenges such as multi-drug-resistant infections, deep tissue infections, and complex biofilm infections. To further break through the bottleneck of antibacterial efficiency, expand the coverage of the antibacterial spectrum, and effectively respond to various bacterial infection scenarios, the combined application of Bi₂S₃ with other materials or effects become a highly promising development trend in the field of antibacterial nanocomposites.

4.4.1. Combined antibacterial effect with traditional antibiotics. The rapid evolution of bacterial resistance, the limitation of the antibacterial spectrum, the imbalance of the bacterial community, the side effects and the limitations of tissue distribution, among other factors, greatly reduce the antibacterial effect of traditional antibiotics. Moreover, most traditional antibiotics have a specific antibacterial spectrum. For instance, penicillins mainly targets Gram-positive bacteria, while aminoglycosides are more effective against Gram-negative bacteria, but are often ineffective against anaerobic bacteria or fungi. This selective killing can disrupt the normal ecological balance of the host's bacterial community and lead to secondary infections. Therefore, combining traditional antibiotics with new nanoreactors for antibacterial purposes has gradually become a new trend in antibacterial resistance.

When Bi₂S₃ nanoreactors are used in combination with traditional antibiotics, they can produce a synergistic effect through multiple mechanisms. Studies show that Bi₂S₃ NPs can interact with the bacterial cell membrane, disrupting their integrity, allowing antibiotics to more easily enter the interior of the bacterial cells, thereby enhancing the antibacterial effect of the antibiotics. For instance, Ma et al. innovatively prepared Bi₂S₃ nanospheres and combined them with antibiotics, achieving significant antibacterial effects. The Zeta potential of the combined system decreases to −5.37 mV (the positive potential of GEN alone), making it easier to adsorb onto the negatively charged bacterial cell membranes. According to high-performance liquid chromatography (HPLC) detection, when Bi₂S₃ is combined with GEN, the content of GEN in MRSA cells increases by 67.8% compared to when GEN is used alone. The bacterial cells show obvious collapse and rupture. The combined antibacterial effect of Bi₂S₃ with GEN or PIP is further investigated by the time-kill method. As shown in Fig. 12b, the growth of MRSA is almost unaffected by 16 µg mL⁻¹ Bi₂S₃ nanospheres alone, while 32 µg mL⁻¹ GEN reduce the count by approximately 0.9 × log₁₀ CFU mL⁻¹ compared to the control. However, the combination of Bi₂S₃ and GEN significantly reduces the regrowth of MRSA, with a 5 × log₁₀ CFU mL⁻¹ reduction in colony count at 24 h compared to GEN alone. In contrast, the combination of Bi₂S₃ and PIP had little effect on the growth of MRSA (Fig. 12c). These results further confirm the synergistic antibacterial effect of GEN and Bi₂S₃. This combined therapy provides an “old drug new use” idea for MRSA infections: by enhancing the activity of ineffective antibiotics through nanoreactors, reducing the cost of developing new antibiotics, and avoiding the rapid evolution of drug resistance. That is, using inorganic nanoreactors to reshape the activity of ineffective antibiotics, with both high efficiency and biological safety, is expected to provide new ideas for the treatment of clinical drug-resistant bacterial infections.⁶³

Fig. 12 (a) pH-based visual colorimetric detection strategy combined with PTT/PDT treatment for S. aureus-infected mice.⁹⁹ Copyright 2021 Elsevier Inc. (b) Time–kill curves of the combinations of Bi₂S₃ (16 µg mL⁻¹) + gentamicin (GEN) (32 µg mL⁻¹) against MRSA. (c) Time–kill curves of the combinations of Bi₂S₃ (16 µg mL⁻¹) +piperacillin (PIP) (512 µg mL⁻¹) against MRSA.⁶³ Copyright 2016 Elsevier Inc. (d) Temperature–time image of solutions with different concentrations of sea urchin-shaped Au@Bi₂S₃ core–shell structures under NIR laser irradiation (808 nm, 2.0 W cm⁻²). (e) ¹O₂ detection of different samples with/without irradiation of NIR light.⁹⁸ Copyright 2020 Elsevier B.V.

4.4.2. Combined antimicrobial effects of photothermal and photodynamic approaches. In the research system combining Bi₂S₃ with antibacterial properties, the photothermal-photodynamic combined antibacterial method, with its unique and highly effective action mode, demonstrates remarkable antibacterial efficacy. Its mechanism of action is closely based on the special photoelectric properties of Bi₂S₃, and it achieves the killing of bacteria through multi-pathway synergy. Bi₂S₃ has an appropriate energy band structure, with its band gap ranging from 1.3 to 1.7 eV. This characteristic endows Bi₂S₃ with the ability to efficiently respond to NIR. In terms of photothermal effect, when exposed to an 808 nm laser or other NIR, Bi₂S₃ absorbs light energy, electrons within the nanoreactors undergo energy level transitions, and then the light energy is converted into heat energy through non-radiative relaxation processes, causing the local temperature to rise rapidly.

Additionally, the Au@Bi₂S₃ core–shell structure prepared by Wang et al. optimizes carrier separation through Schottky junctions and simultaneously exhibits excellent combined antibacterial effects through photothermal and photodynamic mechanisms. Under NIR (808 nm) irradiation, the interaction between photons and the lattice intensifies, causing the lattice vibration to increase and the temperature to rise rapidly. From the UV-Vis-NIR absorption spectrum, Au@Bi₂S₃ has a wide and strong absorption, indicating a high photothermal conversion efficiency. When an 808 nm laser (2 W cm⁻²) is irradiated on different concentrations of Au@Bi₂S₃ suspensions, as the concentration increases, the irradiation time prolongs, or the laser power intensity is increased, the temperature rises rapidly (Fig. 12d). At the same time, this nanocomposite also forms a typical Schottky junction. Under NIR irradiation, electron–hole pairs are generated. Due to the band gap potential of Bi₂S₃ being higher than the Fermi level of gold nanorods (Au NRs), the photogenerated electrons will migrate from Bi₂S₃ to Au NRs, thereby promoting the separation of electron–hole pairs. The separated electrons react with surrounding O₂ to form ˙O₂⁻, while the holes react with OH⁻ to form ˙OH (Fig. 12e). In the antibacterial experiments, under NIR irradiation, Au@Bi₂S₃ exhibited excellent antibacterial activity against E. coli and S. aureus, which indirectly prove the important role of ROS in the photodynamic antibacterial process. When the concentration of Au@Bi₂S₃ reaches the MBC for E. coli and S. aureus, namely 140 µg mL⁻¹ and 120 µg mL⁻¹, after 3 min of 808 nm, 2.0 W cm⁻² NIR irradiation, the bactericidal rate of Au@Bi₂S₃ against E. coli (140 µg mL⁻¹) and S. aureus (120 µg mL⁻¹) was close to 100%, with excellent antibacterial performance.⁹⁸

For clinical application, antibacterial nanoreactors are developing towards functionalization and wearable directions. Dong et al. constructed a wearable colorimetric wound dressing (FBA) in which Rh@Bi₂S₃ nanoflowers (Rh@BS NFs) play a key role in the combined photothermal and antibacterial process (Fig. 12a). Rh@BS NFs, under 808 nm NIR irradiation, convert light energy into heat energy through strong light absorption, causing a local temperature to increase that leads to the denaturation of bacterial proteins and the rupture of the cell membrane, ultimately achieving sterilization. At the same time, under NIR excitation, Rh@BS NFs produce ROS such as ¹O₂, which damage the bacterial cell membrane, DNA, and proteins through oxidation, leading to bacterial death. The combined action of photothermal effect and photodynamic effect, by destroying the integrity of the bacterial cell membrane, inducing protein denaturation and DNA damage, achieves a “double blow”, significantly enhancing the sterilization efficiency. Under low-dose, short-time laser irradiation, efficient sterilization is achieved, and it has good biological safety, providing an experimental basis for precise treatment of bacterial infections.⁹⁹

There is a significant synergistic enhancement effect between photothermal and photodynamic therapy. On the one hand, the high temperature generated by photothermal treatment can accelerate the separation and migration of photogenerated carriers, reduce the recombination of electron–hole pairs, and thereby increase the generation efficiency of ROS. On the other hand, the oxidative effect of ROS can further increase the permeability of the bacterial cell membrane, facilitating the more efficient transfer of heat to the interior of the bacteria, enhancing the antibacterial effect of photothermal treatment on bacteria, which is much higher than the antibacterial efficiency of using photothermal or photodynamic therapy alone. This fully demonstrates the powerful advantages of modified Bi₂S₃ in the combined antibacterial effect of photothermal and photodynamic therapy.

4.4.3. Piezoelectric effect combined with acoustic propulsion for antibacterial purposes. Bi₂S₃ nanocomposites demonstrate diverse antibacterial potential in areas such as photothermal conversion, reactive oxygen generation, immune regulation, and antibiotic synergy. The innovative combination of this nanocomposite with autodynamics’ effects and piezoelectric effects is providing a new technical path to break through the traditional limitations of antibacterial technology. Next we will deeply analyze the synergistic mechanism and antibacterial efficacy of this composite system.

To explore the synergistic antibacterial mechanism of this acoustic force and piezoelectric effect, the design of specific material systems and experimental verification are crucial. For example, Xi et al. prepared Bi₂S₃ (VBS) containing bismuth vacancies by a solvothermal method combined with high-temperature calcination, and grafted phenylboronic acid onto sodium alginate-arginine to form a piezoelectric hydrogel (VBS-PSA) (Fig. 13a). The introduction of cation vacancies significantly enhances the piezoelectric properties of the nanoreactors: the piezoelectric coefficient d₃₃ of undoped Bi₂S₃ (BS) is 19.87 pm V⁻¹, while that of VBS-2 increased to 40.63 pm V⁻¹, an increase of 104%. This also leads to a significant narrowing of the band gap of VBS-2 (Fig. 13b). This improvement results from the charge redistribution caused by the cation vacancies, forming local electric fields, which enhance the charge separation efficiency of the nanoreactors under mechanical stress (Fig. 13c).

Fig. 13 (a) Mechanism of the piezoelectric effect enhancing hydrogel's sonodynamic performance and nano-enzyme activity with the synergistic effect of bacterial killing and osteoblast differentiation promotion. (b) Peroxidase-like (POD-like) at pH = 5.5, the activity of VBS-2 under different US powers. (c) The acoustic induction current curves of different samples. (d) The band gap of BS and VBS was calculated based on the UV-Vis absorption spectra. (e) Analysis of antibacterial properties of different samples under ultrasonic and non-ultrasonic conditions. (f) The residual biofilms of different samples under the presence or absence of ultrasonic conditions. (g) Through the qualitative analysis of protein leakage in different samples under the presence or absence of ultrasonic conditions.¹⁰⁰ Copyright 2025 Royal Society of Chemistry.

Under 1 MHz ultrasound (US) stimulation, the piezoelectric effect of VBS-PSA enhances the sonodynamic efficiency, generating ROS to kill bacteria. The ESR spectrum further indicates that the signal intensity of ˙OH produced by VBS-2 under US is 1.8 times that of BS, verifying the synergistic effect of piezoelectric and sonodynamic on ROS generation (Fig. 13d). Moreover, VBS-PSA exhibit excellent photothermal conversion capabilities under 808 nm NIR (1 W cm⁻²) irradiation: the temperature increases from 25 °C to 54.3 °C within 10 min, and the photothermal conversion efficiency reaches 30.9%. Furthermore, the local high temperature of 54.3 °C further increases the piezoelectric coefficient of VBS-2 by 15%, enhancing the charge separation efficiency under US and increasing the ROS production by 28% compared to at the normal temperature. After the aforementioned processing, Fig. 13e analyzes the antibacterial properties of different samples under the presence and absence of ultrasound conditions. While Fig. 13f is a result of an investigation of the residual biofilm conditions of different samples under the presence and absence of ultrasound conditions. Additionally, Fig. 13g demonstrates the excellent antibacterial performance of the material through the qualitative analysis of protein leakage in different samples under the presence and absence of ultrasound conditions.¹⁰⁰

In addition to regulating the piezoelectric properties through cation vacancies to enhance the synergistic antibacterial effect of sonodynamic and photothermal therapies, the design of heterojunction structures also provides an effective path for the multi-effect synergy of Bi₂S₃-based nanocomposites under combined light and sound stimulation. For example, Yang et al. synthesized BiOCl nanosheets by the solvothermal method and subjected them to thioacetamide sulfidation to form a BiOCl@Bi₂S₃ heterostructure. Under the combined action of 808 nm NIR and US, the photogenerated electrons transfer from the conduction band of BiOCl to the conduction band of Bi₂S₃, while the holes migrate in the opposite direction. The carrier recombination rate is reduced by more than 40% (the PL spectrum shows a 60% decrease in fluorescence intensity). This heterojunction structure enables the nanocomposites to generate stronger photothermal, photodynamic, and sonodynamic effects under combined photoacoustic stimulation.

The surface plasmon resonance effect of Bi₂S₃ enables it to achieve efficient photothermal conversion when exposed to 808 nm NIR (1 W cm⁻²) radiation: A 500 ppm BiOCl@Bi₂S₃ aqueous solution reaches a temperature of 54.3 °C within 20 min. The DCFH-DA probe detection shows that the ROS production under the combined photoacoustic treatment is 265 times and 20 times higher than that of single light or sound treatment respectively. In the field of sonodynamic antibacterial action, 1.0 MHz US (1.5 W cm⁻²) activates BiOCl to produce sonoluminescence, inducing ultraviolet light to excite the semiconductor to generate ROS. When US is combined with NIR, sonoluminescence and light excitation synergistically promote carrier separation, and the electrochemical impedance spectroscopy shows that the charge transfer resistance decreases by 35%. The combined photo-acoustic treatment for 20 min achieves a sterilizing rate of 99.7% for S. aureus and 100% for E. coli.¹⁰¹

5. Potential and therapeutic prospects of Bi₂S₃ nanoreactors

With the long-term and extensive use of antibiotics, the problem of bacterial resistance is becoming increasingly serious, and traditional antibacterial strategies are facing huge challenges. At the same time, medical device-related infections also bring great difficulties to clinical treatment. Though Bi₂S₃-based nanoreactors have not yet entered clinical application, a large number of existing studies have confirmed their significant application potential in addressing these issues; thus, developing such novel and highly effective antibacterial nanoreactors is becoming the key to solving the aforementioned problems.

5.1. Combatting drug-resistant bacterial infections

The rapid evolution of bacterial resistance poses a serious threat to global health. The World Health Organization reports that approximately 700 000 people die each year from infections caused by resistant bacteria, and it is projected that this number will rise to 10 million by 2050.^102–105 The spread of multi-drug resistant strains such as methicillin-resistant MRSA and extended-spectrum β-lactamase-producing E. coli leads to a situation where clinical anti-infection treatments are rendered ineffective. Traditional antibiotics work by inhibiting bacterial cell wall synthesis and interfering with protein translation, but bacteria can rapidly develop resistance through genetic mutations and the acquisition of resistance plasmids. Moreover, the abuse of antibiotics further accelerates this process.

In this context, a new antibacterial strategy based on nanocomposites emerged. Bi₂S₃ exhibits excellent NIR absorption capacity, photothermal conversion efficiency, and photocatalytic activity. It can kill bacteria through multiple mechanisms such as photothermal damage, ROS generation, and ion release, and is less likely to induce the development of drug resistance. More importantly, Bi₂S₃-based nanocomposites can be combined with traditional antibiotics, photodynamic therapy, immunomodulation, etc., to form a synergistic antibacterial effect, providing diversified solutions for dealing with drug-resistant bacterial infections.

For example, Jabbar et al. studied the fabrication of g-C₃N₄ nanosheet immobilized Bi₂S₃/Ag₂WO₄ nanorods. The formed heterojunction has a large specific surface area and abundant active sites, with a redshift in the light absorption edge. It can generate more photogenerated carriers under visible light irradiation. This heterojunction follows the double S-type charge separation mechanism (Fig. 14i). Under visible light (140 W LED) irradiation, the electrons are excited to the conduction band, generating electron–hole pairs. The disinfection kinetics curves of S. aureus under the action of Bi₂S₃, g-C₃N₄, Ag₂WO₄, BS/CN, BS/AW, AW/CN and BS/AW/CN photocatalysts are presented. The results show that the disinfection kinetics of S. aureus can be accurately described by the pseudo-first-order kinetic equation (Fig. 14a). Using S. aureus as the test strain, antibacterial experiments are conducted under visible light irradiation. The results show that in the dark environment, the antibacterial effect of BS/AW/CN on S. aureus is negligible. Under photolytic conditions (140 W LED), BS/AW/CN exhibits excellent antibacterial performance, and can completely destroy the cells of S. aureus within 90 min, damage the cell membranes, leak the contents, and completely inactivate the bacteria, demonstrating excellent antibacterial effects (Fig. 14b). The double S-shaped structure of this nanocomposite endows it with broad-spectrum antibacterial properties. It is also effective against drug-resistant bacteria such as Escherichia coli and Pseudomonas aeruginosa, providing an innovative solution to the global antibiotic resistance crisis. It is expected to play a significant role in environmental governance and clinical medicine.¹⁰⁶

Fig. 14 (a) Study on the first-order kinetics of disinfection by synthetic photocatalysts on S. aureus. (b) Analysis of antibacterial performance of the prepared photocatalyst against S. aureus under LED illumination conditions.¹⁰⁶ Copyright 2023 Elsevier B.V. (c) Kinetic fitting curve of photocatalytic disinfection based on the revised Holm model. (d) Photocatalytic disinfection experiment on E. coli using the prepared samples. (e) The absorption capacity of the as-fabricated samples. (f) The photodegradation of RhB with different samples.⁵⁸ Copyright 2018 Elsevier B.V. (g) H&E staining images showing skin tissue infection degree at 2, 5, and 10 days post-infection. (h) Giemsa staining images showing wound area infection degree on days 2, 5, and 10 post-treatment (scale bars, 50 µm).¹⁰⁸ Copyright 2022 Royal Society of Chemistry. (i) Summary of the antibacterial activity of the BS/AW/CN catalyst compared with previous studies.¹⁰⁶ Copyright 2023 Elsevier B.V.

Similarly, Shi et al. constructed novel Z-type flower-like Bi₂S₃/SnIn₄S₈ heterojunctions in their study. The flower-like structure provides a large specific surface area and abundant active sites, enabling the generation of more photogenerated carriers under visible light irradiation. This Z-type mechanism not only promotes the separation and migration of photogenerated carriers but also maintains a high redox capacity, thereby significantly improving the photocatalytic performance. Using E. coli and S. aureus as test strains, the experimental results show that after 5 hours of visible light irradiation, the Bi₂S₃/SnIn₄S₈-2.5% heterojunction exhibits the highest bactericidal activity (Fig. 14c and d). Under the same conditions, E. coli cells are completely inactivated. Fig. 14e and f show the adsorption capacity of Bi₂S₃, SnIn₄S₈, BS-SIS-1% and so on, and the above results indicate that during the entire photolysis process, the adsorption effect does not play a major role. Furthermore, it is clear that the efficiency of photocatalytic decomposition of RhB is dramatically increased when the BS-SIS-2.5% heterojunction exists in reaction. This further promotes the disruption of the bacterial cell wall by the heterojunction, causing the leakage of substances within the cells and ultimately leading to the loss of bacterial activity.⁵⁸ What deserves special attention is the Sea urchin-like Bi₂S₃/curcumin heterojunction constructed by Danya Wan et al. After 808 nm light irradiation at 0.67 W cm⁻² for 200 seconds, Bi₂S₃/Cur could raise the system temperature from 20.7 °C to 54.5 °C.

The high temperature caused the lipid bilayer of the bacterial cell membrane to phase change and rupture, the intracellular proteins to denature, and ultimately led to the death of the bacteria. Moreover, the redistribution of electrons at the heterojunction interface formed an internal electric field, accelerating the transfer of photogenerated electrons from Bi₂S₃ to Cur, inhibiting electron–hole pair recombination, and promoting the generation of ROS. Among them, the conduction band potential of Bi₂S₃ (−0.37 eV) is higher than the reduction potential of O₂/˙O₂⁻ (−0.33 eV), which could reduce O₂ to ˙O₂⁻ and further to ¹O₂. Through the DCFH-DA probe detection, it is found that the total ROS generated by Bi₂S₃/Cur under light irradiation was significantly higher than that of pure Bi₂S₃ and Cur. ROS can oxidize bacterial cell membrane lipids, proteins, and DNA, such as damaging the sulfhydryl (–SH) group of membrane proteins, resulting in increased membrane permeability, oxidizing DNA bases and triggering mutations, ultimately inducing bacterial death. The Bi₂S₃/Cur heterojunction can reduce the infiltration of neutrophils in infected wounds, reduce the release of inflammatory factors (such as TNF-α, IL-6), and alleviate the inflammatory response. As shown in Fig. 14g, on the 2nd, 5th, and 10th days, the neutrophils in the Bi₂S₃/Cur group were significantly lower than those in the control group and the 3M group, indicating that the inflammatory response at the wound surface of the Bi₂S₃/Cur group was lower. And in Fig. 14h, after Giemsa staining, the bacteria were stained dark blue. From the sections, the number of bacteria in the Bi₂S₃/Cur group was significantly lower than that in the control group and the 3M group on the 2nd, 5th, and 10th days, indicating that the bacterial infection at the wound site on the surface of Bi₂S₃/Cur was less severe. At the same time, its photothermal effect can promote vasodilation, improve local blood circulation, and provide nutritional support for wound healing.^106,107

The Bi₂S₃/Cur heterojunction achieves efficient killing of drug-resistant bacteria through the “photothermal destruction–photodynamic oxidation–curcumin synergy” triple mechanism, promotes wound healing via anti-inflammatory and tissue repair effects, and combines the advantages of semiconductor photocatalysis and natural small molecule antibacterial properties, thus providing a new strategy.

5.2. Prevention of medical device-related infections

Medical devices are widely used in modern medicine, but the accompanying infection problems cannot be ignored. Devices such as urinary catheters,^108–112 artificial joints, and heart stents are prone to bacterial adhesion and the formation of biofilms. The presence of biofilms reduces the sensitivity of bacteria to antibiotics and the body's immune system, making infections difficult to treat and often leading to chronic inflammation and even implant failure, causing great pain and economic burden to patients.

Modifying Bi₂S₃ nanoreactors on the surface of medical devices is an effective strategy for preventing and treating related infections. A Bi₂S₃-based nanocoating can be prepared on the surface of medical devices through methods such as chemical deposition, physical coating, atomic layer deposition (ALD), and magnetron sputtering. In addition, there are atomic ALD and magnetron sputtering methods. The ALD method involves alternating the introduction of gaseous precursors (such as a bismuth source and sulfur source) to perform atomic-level layer-by-layer deposition on the substrate surface. The coating's uniformity and consistency are excellent, and the thickness can be precisely controlled at the nanometer level, making it suitable for high-demand medical implants (such as artificial joints, dental implants). However, the equipment cost is high, the process is complex, and the deposition rate is slow. The magnetron sputtering method utilizes the magnetic field to control the ion bombardment of the plasma on the Bi₂S₃ target and then deposits the sputtered atoms onto the substrate surface to form a coating. The coating has strong adhesion and high purity, and can be deposited at low temperatures, suitable for substrates that are sensitive to heat (such as polymers). It can be used to prepare large-area, highly adhesive Bi₂S₃ antibacterial coatings, but there are currently few reports on its application in the biomedical field, and further exploration is needed.

When Bi₂S₃-based nanoreactors are combined with medical devices, their antibacterial performance remains stable and does not significantly decrease. Animal experiments show that when Bi₂S₃-based nanocoated artificial joints are implanted in rats and observed for 8 weeks, no obvious inflammatory reactions or tissue damage are found, proving that it has good biocompatibility and will not cause significant toxic effects on body tissues. In addition, the degradation products of Bi₂S₃-based nanoreactors in the body, namely bismuth ions, have certain antibacterial activity. Bismuth ions can combine with the sulfhydryl groups in bacteria to inhibit the activity of enzymes and can continuously exert antibacterial effects for a long time, providing a guarantee for the long-term safe use of medical devices.

6. Computational studies on the antibacterial properties of Bi₂S₃-based nanoreactors

Although experimental studies made significant progress in revealing the antibacterial properties of Bi₂S₃-based nanoreactors, the underlying physical and chemical mechanisms still mainly rely on indirect characterization and speculation. The theoretical computational simulation is an effective method for understanding the modification strategies of Bi₂S₃ and its antibacterial mechanism at the atomic and electronic levels. It achieves progress from phenomenological observation to mechanism elucidation and provides a theoretical basis for systematic material design.

The electronic structure and band engineering are the foundation for understanding the piezoelectric response behavior of Bi₂S₃. First-principles calculations (such as DFT (Discrete Fourier Transform)) can accurately obtain the intrinsic band structure, density of states, and edge positions of Bi₂S₃, thereby revealing the electronic origin of its narrow band gap (≈1.3 eV) and visible light absorption properties. However, to quantitatively evaluate the piezoelectric performance of the material under macroscopic mechanical stress, such as the distribution and intensity of the local polarization electric field, finite element simulation is needed. For example, Zhou et al. demonstrated through finite element analysis that in the same ultrasonic stress field, the surface of Bi₂S_3−x particles rich in sulfur vacancies can generate a local potential as high as 0.26 V, much higher than the 0.07 V of the intrinsic Bi₂S₃. The simulation results from the perspective of mechanical–electrical coupling prove that the polarization enhancement induced by sulfur vacancies is the key mechanism for improving charge separation efficiency and catalytic performance. This provides a theoretical basis for understanding the role of defects in piezoelectric catalysis.¹¹³

In the aspect of doping and heterojunction design, DFT simulations can analyze the lattice distortion and charge redistribution caused by dopant elements (such as Ni²⁺), and their regulatory effect on the band structure. When constructing heterojunctions, DFT can predict the charge transfer path at the interface by calculating the work functions and band alignment of each component. For example, Wang et al. discovered through calculation that electrons spontaneously flow from Bi₂S₃ to BiVO₄. This forms an intrinsic electric field from Bi₂S₃ to BiVO₄, driving the Z-type charge transfer mechanism and effectively promoting the separation of photogenerated carriers. Such calculations provide atomic-scale evidence for understanding the formation mechanism of heterojunction types such as Type-II and Z-Scheme. This mechanism successfully guided the design of efficient photocatalytic CO₂ reduction catalysts. This strategy of regulating charge separation through the built-in electric field also provides a theoretical reference for developing other functional materials such as antibacterial nanoreactors.¹¹⁴

In conclusion, theoretical computational simulation has a dual function in the research of Bi₂S₃-based nanoreactors: microscopic scale analysis and design guidance. It can analyze the electronic mechanism behind experimental phenomena and serve as a prediction method to guide the systematic design and optimization of new Bi₂S₃-based nanoreactors with high antibacterial activity and biocompatibility. With the advancement of computational methods and the integration of multi-scale simulations, this complete research mode of theoretical guidance for experiments will play a more important role in the development of antibacterial nanoreactors.

7. Conclusions and prospects

Bi₂S₃-based nanoreactors exhibit significant advantages in the field of antibacterial applications due to their unique physicochemical properties and multiple antibacterial mechanisms. This review systematically explores the synthesis strategies, electronic structure regulation methods, antibacterial action mechanisms and application scenarios of Bi₂S₃-based nanoreactors. Although the Bi₂S₃-based nanoreactors achieve certain progress in the field of antibacterial research, their clinical application and mechanism analysis still face multiple challenges:

(1) Stability: the stability issue of antibacterial nanoreactors is a major challenge that hinders their clinical application. The insufficient dispersion stability of Bi₂S₃-based nanoreactors in the environment can lead to a significant decline in antibacterial activity. When nanoreactors undergo aggregation due to instability, their particle size increases, thereby reducing the efficiency of their interaction with the bacterial membrane. Moreover, the photodegradation phenomenon will intensify the recombination of photogenerated carriers in Bi₂S₃-based nanoreactors, seriously affecting the continuous generation capacity of ROS.¹¹²

(2) Adaptability in complex infection microenvironments: the complex microenvironment at the infection site, including hypoxia, acidic conditions, and biofilm barriers, imposes limitations on the antibacterial efficacy of nanoreactors. The hypoxic environment inhibits catalytic reactions (such as ROS production) that rely on oxygen, thereby weakening the antibacterial activity of nanoreactors; acidic conditions may alter the charge distribution and structural stability of the material surface, interfering with its effective binding with target cells. The physical barrier effect of the biofilm hinders the penetration of nanoreactors, reducing the therapeutic effect.¹¹³

(3) Biological safety: the biological safety of nanoreactors is a prerequisite for their clinical application. Although existing studies have shown that Bi₂S₃-based nanoreactors exhibit good biocompatibility, more in-depth and systematic research is still needed to explore its metabolic pathways in the body and the possible impacts of long-term accumulation on organs such as the liver and kidneys.

(4) Large-scale production: the clinical application of Bi₂S₃-based nanoreactors requires addressing the dual challenges of optimizing the production process and controlling costs. Additionally, achieving large-scale production also necessitates resolving issues such as insufficient material uniformity and differences in stability among batches.¹¹⁵

Looking to the future, relevant research needs to focus on the coordinated development of nanoreactor design innovation, biological safety assessment and clinical application, in order to promote the practical application of Bi₂S₃-based nanoreactors in the field of antibacterial applications (Fig. 15).

Fig. 15 The challenges and feasibility of using Bi₂S₃-based nanoreactors in the field of antibacterial applications.

Author contributions

R. G.: writing – original draft, formal analysis, investigation. H. C.: writing – original draft, formal analysis, investigation. Y. W.: formal analysis, investigation. W. T.: writing – original draft, formal analysis, investigation. H. L.: conceptualization, funding acquisition, project administration, supervision. H. Z.: conceptualization, funding acquisition, project administration, supervision. S. Y.: conceptualization, funding acquisition, project administration, supervision. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

This work received financial support from the National Natural Science Foundation of China (22372001), the National Science Fund for Outstanding Young Scholars of Anhui Province (2408085Y008), and the Starting Fund for Scientific Research of High-Level Talents, Anhui Agricultural University (rc382108).

Notes and references

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Footnote

† These authors contributed equally to this work.

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