Stimuli-responsive photodynamic platforms for the treatment of bacterial infections

Abstract

Bacterial infections caused by drug-resistant bacteria have become a significant health challenge in the 21st century. Photodynamic therapy (PDT), a novel approach for treating drug-resistant bacterial infections, has attracted considerable attention due to its broad-spectrum antimicrobial activity, non-invasive, and highly selective advantages. However, the “always on” nature of conventional PDT often leads to unintended damage to surrounding healthy tissues. To address this issue, stimuli-responsive photodynamic therapeutic (SRPT) platforms with adjustable antibacterial activity have been developed. These SRPT platforms remain inactive in normal tissues and are only triggered to exhibit antimicrobial activity under specific stimuli at the targeted site. This review comprehensively summarizes the contributions of SRPT platforms to the treatment of bacterial infections over the past few years and offers insights into their future development. Specifically, this review delves into the design mechanisms and the latest advancements of SRPT platforms in combating bacterial infections. Particular emphasis is placed on key factors such as pH, redox status, enzymes, and dual-stimulation as the primary design directions for activation strategies.

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Mengyuan Chang

Mengyuan Chang obtained a Bachelor's degree from Jilin University in 2023. He is currently pursuing a Master's degree at Nanjing Tech University. His project is to develop photocatalytic antibacterial materials.

Chunhui Dai

Chunhui Dai received his PhD degree from Nanjing University in 2016. He then did postdoctoral research in Prof. Bin Liu's group at the Department of Chemical and Biomolecular Engineering, National University of Singapore. After that, he returned to China and joined East China University of Technology in 2019. He is now an associate professor and engaged in the development of functional conjugated polymers for photocatalytic conversions and related biological applications.

Dongliang Yang

Dongliang Yang received his PhD degree from Nanjing University of Posts and Telecommunications. Currently, he is an associate professor at the School of Physical and Mathematical Sciences, Nanjing Tech University. His current research interests mainly focus on the development of multifunctional antimicrobial materials for combating microorganism-induced infectious diseases. He has co-authored more than 60 peer-reviewed papers. He is currently the vice editor of Biomedical Engineering Communications and the youth editor of journals such as Research and Exploration.

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1. Introduction

Bacterial infections pose a major global health challenge,¹ causing millions of deaths annually while placing enormous economic strain on healthcare systems worldwide.^2,3 In 2019, bacterial infections caused 7.7 million deaths globally, accounting for over 13% of all deaths that year and making them the world's second leading cause of mortality.⁴ Although antibiotics remain the primary treatment,⁵ their excessive use has accelerated bacterial resistance development.^6,7 This antimicrobial resistance crisis now represents one of modern medicine's greatest challenges.^8–10 In 2021, nearly 4.71 million global deaths were related to bacterial antimicrobial resistance, including 1.14 million deaths directly attributed to bacterial antimicrobial resistance.^11,12 The World Bank estimated that the global GDP would lose at least $1 trillion annually under antimicrobial resistance after 2030, with additional healthcare costs potentially reaching at least $0.33 trillion annually in 2050.^13,14

Biofilm, a community of bacteria,¹⁵ adheres to biotic or abiotic surfaces and is encapsulated by extracellular polymeric substances (EPSs).^16,17 Studies have found that the mechanism of bacterial resistance is inseparable from the formation of biofilms, which is mainly attributed to the defense function of EPSs.^18–20 EPS is composed of polysaccharides, proteins, lipids, and extracellular DNA,^21,22 forming a protective physical barrier. Its compact structure and small pore size hinder antibiotic diffusion,²³ and the polysaccharides in EPS contribute to antibiotic resistance by neutralizing charged antimicrobials.^18,24 Bacterial survival ability is enhanced by EPS to 10–1000 times compared with planktonic bacteria while helping to form a special bacterial microenvironment.^25,26 Moreover, bacteria develop resistance through target site modifications and enzymatic hydrolysis of antibiotic mechanisms.^27–29 Therefore, developing novel treatment strategies that avoid inducing bacterial resistance is critical.

Photodynamic therapy (PDT) offers a unique antimicrobial mechanism that avoids drug resistance development, demonstrating clinical potential in treating tumors, vascular disorders, and microbial infections.^30–33 Unlike antibiotics that kill bacteria by disrupting metabolism and inhibiting nucleic acid, cell wall or protein synthesis,³⁴ PDT directly generates oxidative damage to lipids, proteins, and DNA without triggering antimicrobial resistance.^35,36 Reactive oxygen species (ROS), primary effector molecules of PDT,³⁷ not only mediate antimicrobial action but also activate the host's natural immune defenses against invasion of bacterial infection.^38–40 Due to damaging critical bacterial components like membranes, proteins, and nucleic acids, ROS-driven therapy prevents resistance development through multitarget destruction.^41–45 This dual action stimulates immune activation while accelerating pathogen clearance and tissue repair.

Although PDT has a broad therapeutic prospect, its clinical translation is still limited. Poor targeting specificity leads to off-target drug accumulation in normal tissues, inducing unintended phototoxicity.⁴⁶ Furthermore, continuously active photosensitizers (PSs) also trigger ROS production upon ambient light exposure, thus necessitating strict patient isolation from all light sources.⁴⁷ Developing lesion-targeted stimuli-responsive photodynamic therapeutic (SRPT) platforms has become crucial for precision therapy. Recent advances have yielded SRPT platforms that are activated exclusively by specific physicochemical factors of bacterial infection, like pH changes or enzymatic activity, minimizing off-target effects. Here, we discuss the design strategies of SRPT platforms based on the theoretical principles of PDT and explore the research progress of different activation strategies.

2. Basic principles of PDT

PDT operates through two essential components,⁴⁸i.e., PSs and light, offering non-invasive treatment with low systemic toxicity and negligible resistance development.^30,49,50 PS remains inert until activated by a specific wavelength of light, then it initiates photochemical reactions, generating ROS with cytotoxic properties. Based on the different photochemical reaction pathways, PDT can be divided into two types: type I PDT and type II PDT.

As shown in Fig. 1, PS molecules absorb light energy to transition from the ground state (S₀) to the excited singlet state (S₁) during activation. Through intersystem crossing (ISC), some electrons reach the longer-lived triplet state (T₁), enabling ROS generation via energy/electron transfer, while others return to S₀ with fluorescence emission. Type I mechanisms involve electron or proton transfer from excited PS (S₁) to biological substrates, forming free radical intermediates of both firstly. Then these intermediates react with oxygen molecules or water in the environment to generate ROS (˙OH, O₂˙⁻, H₂O₂). In principle, both the S₁ and T₁ states can participate in these reactions. However, due to the extremely short lifetime (nanosecond order) of the S₁ state compared to the microsecond-scale lifetime of the T₁ state,^51,52 the reaction is dominated by the contribution from the T₁ state. Type II mechanisms feature direct energy transfer from triplet PSs (T₁) to molecular oxygen, yielding highly cytotoxic singlet oxygen (¹O₂) as the predominant lethal agent. The two mechanisms may proceed concurrently, with their relative contributions being influenced by oxygen concentration, PS type, and the specific conditions of the PDT environment.^53,54 Currently, most photosensitizers primarily generate ROS via the type II pathway.⁵⁵ In addition to the two well-known types of PDT, it has also been reported that PSs directly use light energy to destroy genetic information or generate alkyl radicals,^56,57 which also provides an excellent idea and direction for breaking the dependence of oxygen.

Fig. 1 Schematic representation of the mechanisms of photodynamic therapy.

ROS generated during PDT predominantly consist of four cytotoxic agents: hydroxyl radicals (˙OH), superoxide anions (O₂˙⁻), ¹O₂, and hydrogen peroxide (H₂O₂). Among these species, ˙OH demonstrates the highest oxidative damage, exhibiting rapid reaction kinetics with intracellular biomolecules including lipids, proteins, and nucleic acids, thereby inducing substantial cellular damage.^58,591O₂ displays comparable oxidative capacity, preferentially targeting guanine residues in DNA and destroying genetic integrity.^58,60 While H₂O₂ and O₂˙⁻ exhibit relatively moderate oxidative activity, their synergistic action with ˙OH and ¹O₂ establishes a multi-target damage mechanism.⁶¹ This comprehensive oxidative assault, coupled with obvious therapeutic effects compared to conventional antibiotics, significantly impedes the development of microbial resistance.^38,62

SRPT platforms remain “off” in healthy tissues but will turn on at the sites of infection, where they are activated by the specific physicochemical factor of infection microenvironment (e.g., pH, redox substances, enzymes),^63–65 thereby generating ROS under laser irradiation. This activation specificity enables precise ROS generation exclusively at infected sites, significantly improving therapeutic accuracy while reducing side effects on normal tissues.^63,66 At present, aggregation-caused quenching (ACQ), aggregation-induced emission (AIE), förster resonance energy transfer (FRET), photoinduced electron transfer (PET), and inhibition of ISC processes are more common in the design strategies of SRPT platforms (Fig. 2).^67,68

Fig. 2 The photophysical mechanisms of common design strategies of SRPT platforms. Reproduced with permission from ref. 68. Copyright 2025 Wiley-VCH.

The ACQ effect in PSs leads to diminished fluorescence intensity and reduced photodynamic activity when molecular aggregation or supramolecular assembly occurs,⁶⁹ reducing the effect of PDT. The universal approach to overcome the defects of the ACQ effect in PSs is to disrupt the intermolecular packing and break the aggregated state,⁷⁰ thereby enhancing PDT. By applying this strategy to construct SRPT platforms, specific infection microenvironments (e.g., altered pH or enzyme-rich conditions) can disrupt the aggregated state or structure causing the quenching, thereby restoring PS photoactivity for targeted PDT activation. Conversely, certain molecular architectures exhibit the AIE effect, where intermolecular interactions promote radiative decay pathways and fluorescence amplification.^71,72 AIE fluorogens with high ¹O₂ quantum yield are suitable for imaging-guided PDT.⁷³ For FRET-based systems, precise spatial organization is required with donor–acceptor pairs maintaining a 1–10 nm separation distance and sufficient spectral overlap to establish fluorescence quenching.^74,75 Environmental-triggered cleavage of these complexes can restore PS activation, particularly effective for bacterial biofilm penetration and localized antimicrobial PDT. In PET systems, strategically positioned amino groups facilitate intermolecular charge transfer that suppresses fluorescence, while microenvironmental acidification induces amine protonation to reverse the electron transfer process.⁷⁶ Notably, manipulation of ISC efficiency serves as a crucial regulatory mechanism for ROS generation control.^77,78 Pathological biomarkers (e.g., overexpressed enzymes or redox imbalance) can specifically disrupt quencher-PS interactions, achieving dual enhancement of therapeutic specificity and oxidative damage potential.

3. Types of PSs

PDT critically depends on the advancement of PSs, which have undergone transformative evolution from primitive organic dyes to intelligent activatable systems with enhanced targeting capabilities.⁷⁹ The photosensitizing properties of dyes were first observed in the early 20th century. A pivotal breakthrough occurred in 1976 when Kelly and Snell successfully implemented hematoporphyrin derivatives (HpD) for bladder cancer treatment,^80,81 thereby establishing PDT as a viable therapeutic approach. Subsequent research efforts have focused on optimizing three key PS parameters: (1) improving ROS generation efficiency, (2) minimizing systemic toxicity, and (3) activating by near-infrared light for improved tissue penetration.

The evolution of photodynamic agents commenced with the first-generation HpD, including hematoporphyrin sodium and porfimer sodium, which demonstrated clinical potential in solid tumor management.^82,83 Despite their therapeutic efficacy, these early photosensitizers presented three principal constraints: (1) insufficient chemical purity,⁸⁴ (2) prolonged cutaneous photosensitivity usually requiring 6-week post-treatment light restriction protocols,⁸⁵ and (3) limited tissue penetration capacity. These limitations motivated the development of second-generation agents characterized by phthalocyanine and porphyrin-based architectures, exemplified by 5-aminolevulinic acid (5-ALA) and chlorin e6 (Ce6).^83,86 Compared to HpD derivatives, these advanced systems exhibited accelerated metabolic clearance, improved depth-dependent photodynamic action, and enhanced therapeutic outcome.⁸³ Nevertheless, persistent challenges, including aqueous insolubility and suboptimal cellular targeting efficiency, constrain their clinical translation.^47,79 The evolving paradigm in PS design targets dual optimization of tissue distribution and infection-responsive activation to circumvent the pharmacokinetic constraints of previous generations (Fig. 3).⁸⁷

Fig. 3 The development progress represented by porphyrin: porphyrin (the first-generation); temoporfin (the second-generation); ATPP-TPE (smart generation of 5-(4-aminophenyl)-10,15,20-triphenylporphyrin with tetraphenylethene to surmount ACQ). Reproduced with permission from ref. 88. Copyright 2020 Wiley-VCH.

Despite significant advancements in PS design, several inherent challenges persist, limiting their therapeutic efficacy, specificity, and clinical translation. These main issues can be broadly categorized as follows: (1) poor target specificity and off-target effects: conventional PSs often lack inherent selectivity for bacterial cells or infection sites over host tissues.⁸⁷ This poor targeting leads to unintended accumulation in healthy tissues. (2) “Always-on” nature and dark toxicity: most traditional PSs remain pharmacologically active regardless of their location. They can generate ROS or exhibit cytotoxic effects even without light activation in some cases (dark toxicity).⁵⁸ (3) Limited tissue penetration of excitation light: most clinically approved and widely studied PSs (e.g., porphyrin derivatives, methylene blue, chlorin e6) have absorption maxima in the visible light range (400–700 nm).⁶⁵ Light in visible light region has limited tissue penetration depth due to scattering and absorption by endogenous chromophores (e.g., hemoglobin and melanin). Advance understanding of infection microenvironments has elucidated critical pathophysiological distinctions between infected and healthy cells, informing novel PS design strategies. Infection tissue exhibits four main hallmark microenvironmental characteristics: (1) acidic pH gradients, (2) elevated glutathione (GSH) concentrations, (3) enzyme overexpression (e.g., lipase, nitroreductase, and aminopeptidase), and (4) dysregulated redox homeostasis. Capitalizing on these phenomena, researchers have developed SRPT platforms that maintain minimal ROS generation/drug release under physiological homeostasis, yet exhibit selectively enhanced ROS production/drug release exclusively through infection microenvironment-specific triggers, achieving precise three-dimensional spatiotemporal control of oxidative activity. This microenvironment-driven strategy achieves pathogen-selective photodynamic action/drug release while preserving adjacent healthy tissue integrity, which offers a breakthrough solution to conventional PDT's longstanding selectivity limitation.

Activatable PDT addresses two critical limitations of conventional PDT: off-target phototoxicity and insufficient selectivity. Notably, the clinical trials of these smart PS platforms now extend beyond oncology, with emerging applications in combating multidrug-resistant bacterial infections through infection microenvironment-targeted activation.⁸⁹ These platforms achieve precise spatial and temporal control of ROS generation by responding to unique pathological features such as acidic pH, specific enzymes, or hypoxia at infection sites, while maintaining excellent biocompatibility with host tissues, offering a powerful alternative to conventional antibiotics in the era of growing antimicrobial resistance.

4. Recent advances in the SRPT platforms

Current research has identified five distinct pathophysiological characteristic of infection microenvironments that can serve as biochemical triggers for targeted photodynamic therapy: (1) acidic pH gradients enabling protonation-dependent activation, (2) enzyme overexpression facilitating substrate-specific cleavage, (3) toxin-mediated membrane permeabilization enhancing PS internalization, (4) dysregulated redox homeostasis with characteristic glutathione fluctuations and ROS generation, and (5) accumulation of other specific disease biomarkers. These characteristics enable smart PS design through three activation modalities: pH-responsive conformation switching, enzyme-catalyzed prodrug conversion, and redox-triggered electron transfer cascades.^90,91 This microenvironment-targeted strategy achieves dual therapeutic precision through pathogen-specific ROS generation and adjacent host tissue preservation, effectively overcoming the non-selective cytotoxicity inherent to conventional PDT.

4.1. Chemical microenvironment-responsive SRPT platforms

4.1.1. pH-Responsive platforms for acidic microenvironment targeting. Bacterial infection typically exhibits an acidic microenvironment with pH values ranging from 5.0 to 6.5, primarily attributed to lactic acid accumulation from microbial metabolism.^92,93 This distinct pH profile differentiates infected tissues from normal surrounding tissues, enabling the strategic development of pH-responsive PDT systems. By restricting therapeutic activation to acidic conditions, such targeted approaches can minimize off-target phototoxicity while maintaining treatment efficacy at infection sites.

Acid-sensitive molecular systems can be engineered to create an SRPT platform that selectively activates in acidic microenvironments. These compounds remain inert in normal tissues but undergo structural cleavage at infection sites, triggering the release of PSs. Subsequent laser irradiation induces ROS generation from the activated PSs, enabling targeted bacterial eradication. Common acid-labile functional groups include ester bonds, amine moieties, ether linkages, and amide derivatives.⁹⁴ Hu et al. developed a surface charge-switchable supramolecular nanocarrier (α-CD-Ce6-NO-DA) that combines pH-responsive PEG-polypeptide copolymers with α-cyclodextrin prodrugs for targeted biofilm therapy (Fig. 4a).⁹⁵ α-CD-Ce6-NO-DA maintains negative surface charge at physiological pH (7.4), ensuring stable blood circulation, while amido bond cleavage and switching to positive charge in acidic biofilm environments (pH 5.5) to enhance biofilm penetration and bacterial adhesion (Fig. 4b). This pH-dependent charge reversal mechanism resolves the long-standing conflict between circulation stability and penetration efficiency in conventional cationic nanocarriers, offering a new solution for precision drug delivery. Experimental results demonstrate a remarkable 99.9% eradication of MRSA biofilms under low-dose conditions (Ce6 10 μg mL⁻¹) with mild laser irradiation (0.2 W cm⁻²) (Fig. 4c), while causing negligible damage to healthy tissues (Fig. 4d). This microenvironment-responsive delivery system provides a promising strategy for overcoming biofilm antibiotic resistance and achieving targeted antimicrobial therapy.

Fig. 4 (a) Schematic illustration of α-CD-Ce6-NO-DA nanocarriers. (b) Structure and charge reversal of PEG-(KLAKLAK)₂-DA at pH 5.5. (c) In vitro bactericidal rates of different treatments with different concentrations. (d) In vitro cytotoxicity of NIH 3T3 fibroblast cells after incubation with different treatments. Reproduced with permission from ref. 95. Copyright 2020 American Chemical Society.

In another study, Lei et al. used a microneedle patch to deliver antibacterial agents, which can penetrate the stratum corneum to the epidermis or dermis without touching the capillaries and nerve endings.⁹⁶ The biodegradable microneedle patch is loaded with a self-encapsulated micelle consisting of a pH-responsive polymer (DMA-PEI-PLGA, DPP) and chlorin e6 (Ce6) conjugated to an antimicrobial peptide that can be used to eradicate traumatic bacterial infections and promote wound healing. When reaching the acidic microenvironment of infection tissue, the amide bonds between 2,3-dimethylmaleic anhydride (DMA) and PEI rupture, micelles decompose, and drugs are released (Fig. 5a), antimicrobial peptides bind to bacterial cell membranes, and Ce6 can produce ROS under light irradiation and play a synergistic role with antimicrobial peptides. In vivo experiments showed that diabetic mice infected with S. aureus were treated with microneedle patches on the wounds, and the wounds were completely healed within 15 days under light irradiation (Fig. 5b).

Fig. 5 (a) Schematic diagram of self-assembly, pH charge conversion, and decomposition of micelles. (b) Relative wound healing area of the mice receiving different treatments. Reproduced with permission from ref. 96. Copyright 2023 Elsevier. (c) Schematic illustration of RB@PMB@GA nanoparticles for pH-responsive PDT. (d) CLSM images of the P. aeruginosa biofilms after different treatments. Reproduced with permission from ref. 97. Copyright 2021 Wiley-VCH. (e) SEM images of MRSA biofilms after different treatments. Scale bar: 2 μm. Reproduced with permission from ref. 98. Copyright 2024 Wiley-VCH.

The surface of the drug carries a negative charge, which can reduce the uptake of cells, reduce dark toxicity to normal tissues, and increase biocompatibility. By introducing the protonable groups, these drug nanocarriers not only possess favorable safety but also enhance both acidic microenvironment compatibility and biofilm targeting for superior bacterial eradication. For example, Wu et al. designed a pH-responsive antimicrobial nanoplatform (RB@PMB@GA) by covalent combination of propylamine-functionalized photosensitizers Rose Bengal and polydopamine.⁹⁷ The nanoparticles, which are negatively charged at normal physiological pH, exhibit good biocompatibility and low cytotoxicity, effectively avoiding non-specific uptake and potential toxicity in normal tissues. However, in the acidic microenvironment of the infection site, the surface charge of RB@PMB@GA is reversed to positive through pH-sensitive electrostatic interactions (Fig. 5c), which significantly enhances the affinity of the nanoparticles with the outer membrane of negatively charged Gram-negative bacteria, thereby promoting the efficient penetration into biofilm and achieving precise bacterial killing. This result also was confirmed by confocal laser scanning microscopy (CLSM) imaging analysis (Fig. 5d), in the P. aeruginosa biofilms, only faint red fluorescence was detected at pH 7.4; while RB@PMB@GA penetration was better at pH 5.0, with a fluorescence ratio of 93%. This result indicated that RB@PMB@GA carries a positive charge in an acidic microenvironment, which facilitates adherence to bacterial surfaces and infiltrates biofilms. In vivo experiments have shown that RB@PMB@GA shows good osmotic ability, which can effectively eliminate biofilms, reduce inflammation, and improve treatment effects.

Similarly, Sun et al. synthesized pH-responsive nanosystems using a pyridine betaine group that can protonate and charge invert under acidic conditions to modify hollow mesoporous organosilica nanoparticles (HMONs-PyB) to enhance the ability of penetrating biofilms.⁹⁸ Simultaneously, both AIE-based TAPI photosensitizers (i.e., an organic small molecule consisting of an electron-donating N,N-bis(4-methoxyphenyl)aniline group, a π-conjugated thiophene bridge, and an electron-accepting 3-(dicyanomethylene)indane-1-one moiety) and lauric acid (LA) were co-encapsulated within HMONs-PyB. Within this system, TAPI formed highly crystalline self-aggregates in the LA matrix. AIE/LA@HMONs-PyB significantly enhanced TAPI's photosensitizing efficiency when encapsulated in the HMONs-PyB (Fig. 5e). In addition, AIE/LA@HMONs-PyB can also promote the recovery of chronic wounds in diabetic mice by reducing inflammation and promoting angiogenesis, which provides an important idea for the clinical treatment of chronic wounds.

In addition, unlike conjugating acid-sensitive groups directly in PSs, this method is simpler and easier to prepare by using acid-sensitive carriers to load or encapsulate PSs. Xiu et al. synthesized a new multifunctional therapeutic diagnostic nanoplatform (MBP-Ce6 NSs) for pH-responsive antimicrobial strategies.⁹⁹ Specifically, manganese dioxide (MnO₂) nanosheets are modified with bovine serum albumin and polyethylene glycol to load Ce6 to obtain MBP-Ce6 NSs, which enables dual-mode imaging and enhanced antibacterial effect under hypoxia (Fig. 6a). Here, the MnO₂ nanosheet as a carrier can not only load Ce6, but also act as a catalyst to catalyze the decomposition of the high concentration of H₂O₂ in the infected tissue to O₂, thereby enhancing PDT. When MBP-Ce6 NSs are delivered to acidic infected tissues, Mn²⁺ generated by the decomposition of MBP-Ce6 NSs can generate T₁-weighted MRI signals, and the released Ce6 can generate fluorescent signals under light excitation, thus achieving dual-mode imaging in the infected tissue. In vitro and in vivo experimental results indicated that MBP-Ce6 NSs have a good effect on the treatment of MRSA-infected diseases, which can provide a promising diagnostic and therapeutic platform for bacterial infection. Differently, in response to the poor water solubility of Ce6, Yan et al. prepared ultra-thin hollow silica nanoparticles (UHSN@CS-Ce6) using chitosan (CS)-modified silica nanoparticles loaded with Ce6 (Fig. 6b).¹⁰⁰ The hollow silicon nanoshell was only 10 nm thick, and the drug loading efficiency was up to 80.6% after modification. Moreover, the hollow silica nanoshell could release the loaded Ce6 responsively at acidic pH due to the protonation of chitosan. In vitro experiments showed that UHSN@CS-Ce6 had more than 20% higher antibacterial effect than free Ce6, and in vivo experiments showed that UHSN@CS-Ce6 promoted skin wound healing. This pH-responsive nanoparticle is a potential therapeutic strategy for the treatment of skin infections.

Fig. 6 (a) The preparation of MBP-Ce6 NSs and antibacterial PDT process of bacterial biofilm infections. Reproduced with permission from ref. 99 Copyright 2020 American Association for the Advancement of Science. (b) The preparation of UHSN@CS-Ce6. Reproduced with permission from ref. 100 Copyright 2021 Elsevier.

4.1.2. Redox-responsive platforms for oxidative stress modulation. Cellular redox homeostasis, defined as the dynamic equilibrium between oxidizing agents (e.g., ROS) and reducing agents (e.g., GSH), undergoes significant dysregulation during bacterial infections.¹⁰¹ In response to bacterial infection, phagocytes assemble and activate NADPH oxidase to produce a large amount of O₂˙⁻.¹⁰² This redox imbalance creates a distinct physiological environment from healthy tissues; for example, infection microenvironments typically exhibit higher ROS concentrations coupled with compensatory antioxidant upregulation.¹⁰³

Redox-responsive antibacterial platforms have emerged as a promising strategy for precision antimicrobial PDT. Relative designs of SRPT platforms can leverage these microenvironmental peculiarities through three activation mechanisms: (1) ROS-responsive bond cleavage (e.g., thioketal linkers), (2) GSH-triggered disulfide reduction, and (3) enzyme-mediated redox cycling. Recent advances demonstrate that redox-activatable PSs maintain inertness in healthy tissues while achieving >90% activation specificity in infected regions, as evidenced by multiple research groups.

4.1.2.1. GSH-responsive systems for reducing microenvironment targeting. GSH-activated SRPT platforms achieve selective PS activation by exploiting the elevated GSH concentration. The predominant design strategy involves incorporating GSH-responsive moieties-particularly disulfide bonds or other thiol-reactive groups-directly into the PS structure to enable targeted activation. When these molecules are exposed to GSH, they undergo a reductive reaction that activates PSs, resulting in the production of ROS by laser irradiation at the lesion site, which results in bacterial structure destruction. Li et al. developed a dual-cascade tumor-responsive multifunctional nanoparticle Gem/Emo@NP@GHA that enables precise antibacterial and antitumor combination therapy through GSH-responsive mechanisms (Fig. 7).¹⁰⁴ The core of the NPs consists of a GSH-sensitive disulfide-bonded biopolymer, encased with gemcitabine (Gem) and two-photon photosensitizer emodin (Emo), and an outer layer of hyaluronidase-responsive guanidinium functionalized hyaluronic acid (GHA). After the GHA shell is degraded by hyaluronidase, the exposed core nanoparticles (Gem/Emo@NP) carry a positive charge, facilitating their penetration through the dense tumor tissue. After entering the inside of the lesion, the intracellular high concentration of GSH rapidly destroys the disulfide bond structure of the core, triggering the release of Gem and Emo, effectively avoiding drug inactivation caused by bacterial metabolism. In vitro experiments showed that Gem/Emo@NP@GHA released in response to GSH exhibited 99.94% clearance efficiency against common E. coli Nissle 1917 (EcN) strains in pancreatic cancer through a synergistic killing of bacteria by membrane depolarization and photodynamic generation of monomeric oxygen. This GSH-responsive cascade release strategy not only overcomes bacteria-induced chemoresistance but also provides a novel nanoplatform with precise antibacterial and immune activation functions for the treatment of infectious tumors.

Fig. 7 Schematic illustration of the preparation and cascade-responsive mechanism of Gem/Emo@NP@GHA. Reproduced with permission from ref. 104 Copyright 2025 Wiley-VCH.

4.1.2.2. ROS-responsive systems for oxidative damage amplification. ROS are highly oxidative molecules that exist at low basal levels in normal cells and tissues. However, bacterial infections or other pathological conditions induce metabolic dysregulation, leading to excessive ROS production. This pathological feature enables the design of ROS-responsive nano-PSs that undergo selective activation in high-ROS environments, thereby achieving targeted PDT effects. Duan et al. proposed a ROS-responsive theranostic platform by using IR820 dye and calcium ion sealed porous silicon (I-CaPSi) for the treatment of chronic wound infection (Fig. 8a).¹⁰⁵ When IR820 was efficiently loaded in porous silicon matrix by the one-pot calcium silicate capping method, porous silicon (PSi) underwent oxidative degradation under the stimulation of ROS, triggering IR820 release and accompanying photothermal signal changes (Fig. 8b). In the antibacterial activity, I-CaPSi exhibited a high bactericidal efficiency of 92.5% against S. aureus under near-infrared (NIR) irradiation through enhanced photothermal conversion efficiency (52.2%) and photodynamic effect to generate a large amount of ¹O₂, which synergistically destroyed the bacterial cell membrane structure. In the diabetic mouse infection model, I-CaPSi dressing effectively eliminated wound bacteria through NIR-triggered photothermal and PDT. Combined with the ROS-responsive photothermal signal monitoring function, I-CAPSi dressing reduced the wound area to 4.24% and can dynamically reflect the wound healing status by measuring the change of photothermal signal of I-CaPSi. The platform integrates ROS response, antibacterial, repair, and good biosafety, providing a new integrated diagnosis and treatment strategy for chronic wound management.

Fig. 8 (a) Schematic illustration for the release of IR820 in PSi. (b) Schematic illustration of the ROS-responsive mechanism of I-CaPSi. Reproduced with permission from ref. 105. Copyright 2023 Elsevier. (c) Schematic illustration for the structure of PSs with different numbers of introduced cations and the process for antibacterial PDT. (d) Images of mouse wounds after different treatments. (e) Quantitative analysis of MPO and CD31 from different treated groups. Reproduced with permission from ref. 106. Copyright 2024 Wiley-VCH.

Compared with IR820 with photothermal properties, cationic PSs have greater potential in penetrating biofilms, Li et al. developed a collaborative therapeutic platform based on ROS-responsive core–shell microneedle (HB-TTP&EGF@MN), which utilizes multi-cationic long chain PSs (HB-TTP) and achieves the dual goals of efficient antibacterial and tissue regeneration through a spatially and temporally controlled drug release strategy (Fig. 8c).¹⁰⁶ The microneedle system consists of a hyaluronic acid (HA) shell and a ROS-responsive hydrogel core loaded with the cationic photosensitizer HB-TTP and epidermal growth factor (EGF), respectively. When the MNS penetrates the biofilm, the shell rapidly lyses and releases HB-TTP, whose multi-cationic long-chain structure is anchored to the bacterial surface through electrostatic interactions and efficiently generates ROS by a type I/II photodynamic mechanism under 635 nm laser excitation. Compared with conventional PSs, cationic modification of HB-TTP significantly reduces the energy level difference between singlet and triplet states and prolongs the lifetime of the triplet state, thereby maintaining efficient ROS generation ability under hypoxic conditions. The core of the microneedles is slowly degraded in the endogenous ROS environment of the wound to achieve sustained EGF release and promote epithelialization and angiogenesis. In the mouse infection model, the HB-TTP&EGF@MN treatment group combined with laser irradiation achieved a wound healing rate of more than 95% within 7 days (Fig. 8d), and histological analysis showed that new collagen fibers were tightly arranged and inflammatory cell infiltration was reduced. Immunofluorescence staining further confirmed that it accelerated wound healing by inhibiting myeloperoxidase (MPO) expression and promoting CD31-labeled angiogenesis (Fig. 8e). In this study, the combination of a multi-cationic PS designed by molecular engineering strategy and ROS-responsive microneedles not only solves the problem of biofilm penetration and photodynamic efficiency in a hypoxic environment, but also realizes the synergistic effect of antibacterial and repair through the sequential release mechanism, which provides innovative ideas for the treatment of chronic infectious wounds.

In addition, hypochlorous acid (HClO) is an endogenous ROS secreted by phagocytic cells to defend against bacterial invasion.¹⁰⁷ Therefore, HClO can be used as a specific stimulator for personalized bacterial infection treatment. Wu et al. designed HClO-activatable nanoprobe DTF-FFP NPs,¹⁰⁸ and the near-infrared molecule FFP responding to HClO and the PS DTF with AIE properties were encapsulated by the surfactant F127 through nanoprecipitation (Fig. 9). FFP can quench the fluorescence of DTF and the production of ROS, but when the probe is delivered to the site of infection, endogenous HClO will degrade FFP, liberating DTF for diagnosis and PDT.

Fig. 9 The preparation process of DTF-FFP NPs and schematic representation of the HClO response mechanism of DTF-FFP NPs. Reproduced with permission from ref. 108. Copyright 2020 Wiley-VCH.

4.1.3. Enzyme-responsive platforms for substrate-specific activation. During invasion, pathogenic bacteria secrete abundant hydrolytic enzymes (e.g., hyaluronidase) to degrade extracellular matrix components, thereby compromising host structural integrity and overcoming innate immune barriers.¹⁰⁹ Concurrently, proliferating bacteria express diverse extracellular proteases (e.g., metalloproteinases and serine proteases) to hydrolyze host-derived macromolecules—including membrane proteins and structural components like collagen and fibronectin—thereby acquiring essential nitrogen and carbon nutrients.¹¹⁰ This pathogen–host interaction mechanism markedly upregulates enzymatic activity within the infection microenvironment. Leveraging this pathological signature, an enzyme-responsive PDT system can be engineered by incorporating substrate-specific or enzyme-cleavable linkers.
4.1.3.1. Nitroreductase-rsponsive systems for deep-tissue infection targeting. Nitroreductases (NTRs) are abundantly expressed across diverse bacterial species, including clinically relevant pathogens such as S. aureus, Pseudomonas aeruginosa, and Enterobacteriaceae.¹¹¹ These NTR-producing bacteria are frequently implicated in nosocomial infections and often exhibit resistance to conventional antibiotic therapies.¹¹² NTR levels are not high in eukaryotes, so NTR can be used as bacterial-specific stimulatory factors.^111,113 Based on this, Ran et al. constructed NTR-activated theranostic nanoparticles mSC-nMB@BM NPs by modifying methylene blue (MB) PSs with 4-nitrobenzyl chloroformate as a trigger switch (Fig. 10a).¹¹⁴ Bacterial membranes were used to encapsulate luminescent material-modified mesoporous silica (mSC) and NTR-activatable methylene blue (nMB). Under the action of bacterial pore-forming toxins, nMB and mSC could be released, then nMB was converted to photosensitive MB by interaction with NTR. Ultrasound-activated mSC emission light source enables MB to produce ROS inside the bacteria (Fig. 10b), enabling more efficient PDT (Fig. 10c). Therefore, this treatment strategy can achieve more precise treatment in deep infected tissues, effectively reduce the toxic side effects caused by drugs, and provide a new idea for the specific diagnosis and treatment of deep tissue infection.

Fig. 10 (a) Schematic illustration of preparation and responsive mechanism of mSC-nMB@BM. (b) Sonoluminescence spectra of mSaoe (mesoporous silica deposited with SrAl₂O₄:Eu²⁺), mSC, and mSC-nMB@BM. (c) Antibacterial rate with different treatment. Reproduced with permission from ref. 114. Copyright 2024 Wiley-VCH.

4.1.3.2. Aminopeptidase-responsive systems for Pseudomonas aeruginosa biofilm eradication. Aminopeptidases (APs) are commonly found in bacteria and play roles in various cellular processes, including the intracellular degradation of proteins. In specific bacterial species, these enzymes localize to cell membranes where they facilitate signal transduction and promote bacterial proliferation.¹¹⁵ During infection, pathogenic bacteria upregulate the production of APs to hydrolyze host cell proteins, facilitating nutrient acquisition and creating space for bacterial colonization. Different bacterial species express distinct types of APs. For instance, Pseudomonas aeruginosa aminopeptidase (PaAP) is a unique enzyme that serves as a key component of this pathogen's biofilm structure.¹¹⁶ During mature biofilm stages, PaAP contributes to biofilm biomass maintenance through nutrient recycling mechanisms.¹¹⁷ PaAP deficiency triggers bacterial cell death and significantly destabilizes biofilm architecture.^116,117 Given the critical role of PaAP in P. aeruginosa drug resistance, Liu et al. synthesized a near-infrared PS, Cy-NEO-Leu.¹¹⁸ The leucine (Leu) group was used as a responsive group, forming Cy-NEO-Leu with heptamethine cyanine (Cy) and neomycin (NEO). When Cy-NEO-Leu reached the infection site, it was activated by PaAP and converted to Cy-NEO-NH₂ with both photothermal and photodynamic effects (Fig. 11). Under laser irradiation, Cy-NEO-NH₂ can achieve antibacterial and anti-biofilm effects by disrupting the transcription and translation of P. aeruginosa and simultaneously enhance the immune response to promote wound healing.

Fig. 11 Schematic illustration of PaAP-responsive Cy-NEO-Leu activation and therapeutic mechanisms. Reproduced with permission from ref. 118. Copyright 2024 American Chemical Society.

4.1.3.3. Hyaluronidase-responsive systems for extracellular matrix degradation and drug release. Hyaluronidase (HAase) is widely distributed in microorganisms and is involved in the bacterial infection process, which can facilitate bacterial invasion through extracellular matrix (ECM) degradation, disrupting tissue barriers, and the degradation products can also serve as a carbon source in the bacterial multiplication process.^119,120 Yuwen et al. synthesized HAase-responsive phototheranostic nanoparticles after Ce6-modified hyaluronic acid (HA) was loaded into MoS₂ nanosheets.¹²¹ In the absence of HAase, the fluorescence of Ce6 was quenched and the photodynamic performance turned off the function of the PS. When the exposure to HAase, HA is degraded and Ce6 is released to exert the photodynamic effect. Two years later, the same group developed multifunctional nanotherapeutic HA-Ce6-MNZ NPs.¹²² It can also be activated in response to HAase in the bacterial microenvironment, and was combined with the chemical drug metronidazole (MNZ) to enhance antibacterial and anti-biofilm under hypoxic conditions (Fig. 12). Firstly, Ce6 can directly kill the metabolically active MRSA in the surface layer under light irradiation. Meanwhile, by consuming oxygen, PDT further enhanced the internal hypoxic microenvironment of the biofilm, which induced the expression of bacterial NTR. Subsequently, the antibacterial effect of MNZ was activated to eradicate the bacteria in the deep layer of MRSA biofilms. In vivo, HA-Ce6-MNZ NPs were applied to the chronic wounds of diabetic mice, achieving 99.999999% bacterial clearance, promoting wound healing by facilitating the polarization of macrophages to the reparative M2 phenotype and accelerating collagen deposition and epithelial regeneration.

Fig. 12 Schematic illustration of preparation and theranostic process of HA-Ce6-MNZ NPs. Reproduced with permission from ref. 122. Copyright 2022 Springer Nature.

4.1.3.4. β-Lactamase-responsive systems for overcoming antibiotic resistance. β-Lactamase, a resistance enzyme expressed by diverse bacterial species, hydrolyzes β-lactam antibiotics through cleavage of the β-lactam ring.¹²³ This enzymatic inactivation renders cephalosporins ineffective against β-lactamase-producing pathogens.¹²⁴ Notably, this resistance mechanism can be leveraged to construct β-lactamase-responsive PSs, enabling targeted activation at infection sites. For MRSA that produces β-lactamase, Xu et al. designed a near-infrared probe CySG-2 for imaging-guided PDT,¹²⁵ which was synthesized from an intermediate product of cephalosporin antibiotic (GCLE) and a heptamethine cyanine dye with lipophilic and cationic properties.

GCLE can be hydrolyzed by β-lactamase and the fluorescence intensity of CySG-2 was recovered. Then, under 808 nm laser irradiation, a large number of ROS were generated, which effectively destroyed the bacterial membrane structure. This therapy can achieve both diagnosis and treatment dual functions, providing a new idea for the treatment of drug-resistant bacteria. Similarly, Li et al. synthesized an activatable PS of Ce-OHOA using an ether bond to link the 4-hydroxyl-oxoisoaporphine (OHOA) and cephalosporin (Ce) (Fig. 13a).^126,127 Ce-OHOA exhibited low ¹O₂ yield and fluorescence quantum yield in physiological environments, but showed excellent yields after hydrolysis by β-lactamase. Molecular docking analysis revealed a hydrogen bond interaction between Ce-OHOA and Ser70, Ser130, Ser235, Ala237, and Ser244 of β-lactamase, the active site of β-lactamase, ensuring a specific activation mechanism. Moreover, in vivo experiments showed that Ce-OHOA-treated MRSA-infected rats had significantly faster wound healing (Fig. 13b), reduced inflammatory infiltration in tissue sections, and enhanced collagen regeneration.

Fig. 13 (a) Schematic illustration of Ce-OHOA for selective activation and photodynamic antibacterial therapy. (b) Successive photographs of wounds with different treatments. Reproduced with permission from ref. 126. Copyright 2024 Elsevier. (c) Schematic illustration of the preparation and PDT process of MMP-S NPs. Reproduced with permission from ref. 130. Copyright 2020 Elsevier.

4.1.3.5. Matrix metalloproteinase-responsive systems for ocular infection therapy. Matrix metalloproteinases (MMPs) are widely present in mammals and are mainly involved in the degradation and remodeling of the extracellular matrix (ECM).¹²⁸ When bacteria invade, the host immune system activates the inflammatory response, which prompts neutrophils and macrophages to release MMPs and degrade the local ECM to help immune cells migrate to the site of infection.¹²⁹ Therefore, MMPs overexpressed at the site of bacterial infection can be used as a trigger factor for specific PDT treatment of infected tissues. Han et al. developed an MMP-9-responsive supramolecular nanoparticle (MMP-S NP) to achieve efficient treatment of bacterial keratitis by PDT (Fig. 13c).¹³⁰ MMP-S NPs were constructed by self-assembly of Ce6β-modified cyclodextrin and an aptamer containing an MMP-9 sensitive peptide. In the normal ocular surface microenvironment, the peptides on the surface of nanoparticles give them negatively charged characteristics, which can avoid nonspecific binding to negatively charged mucin and prolong the tear retention time. When nanoparticles reached the site of infection, MMP-9 overexpressed in the infection microenvironment specifically clefts relative peptide segments, removing the protective peptide shell and exposing the cationic peptide. In vitro experiments showed that MMP-S NPs activated by MMP-9 could efficiently produce ROS under 660 nm light, and the bactericidal rates of P. aeruginosa in planktonics and biofilms were 99.9% and 99.997%, respectively. Notably, MMP-S NPs showed good biocompatibility both in vitro and in vivo, and did not cause toxic reactions in blood indicators or major organs.

4.2. Pathogen-specific responsive platforms

4.2.1. Toxin-responsive platforms for bacterial secretion-mediated activation. Toxins serve as key mediators of bacterial invasion, directly contributing to host tissue damage and exemplifying bacterial pathogenicity. Due to their consistent presence during infection, these toxins represent ideal targets to construct the responsive therapeutics. Zhuge et al. developed a biomimetic nanobubble with good biocompatibility,¹³¹ which uses a red blood cell membrane to encapsulate oxygen-dissolved perfluorocarbon nanoemulsion and PS IR780. After the nanobubbles enter the body and absorb toxins from bacteria such as MRSA, leading to pore formation on their surface and subsequent release of dissolved oxygen and photosensitizers. This process enhances PDT efficacy and improves bactericidal activity. In vitro assays further confirmed that this approach reduces tissue lesions and mitigates inflammatory responses.

4.3. Dual stimulus-responsive platforms

To improve the targeting precision of responsive phototherapy platforms, researchers have developed dual-stimuli-responsive photodynamic therapeutic platforms. These systems remain inactive until triggered by two specific physiological signals simultaneously. Unlike single-factor-activated therapies, this dual-activation mechanism significantly enhances treatment specificity by ensuring that the system only activates in the presence of both pathological cues. For example, under normal physiological conditions—or when only one stimulus is detected—the system remains inert, preventing premature activation. However, upon concurrent detection of dual biomarkers—typically the pathological pH gradient and overexpressed enzymes at the disease site—the system activates, delivering its targeted antibacterial effect.

4.3.1. pH/lipase-dual responsive platforms for sequential drug release and biofilm penetration. Bacterial lipase mediates host lipid breakdown into metabolizable substrates while reshaping the infection microenvironment through released lipid derivatives. In biofilm-forming pathogens, it additionally functions as a virulence factor supporting matrix development. As a representative example, Yang et al. developed an amphiphilic ciprofloxacin (CIP)-betaine conjugate (CIP-CB) through an ester bond between CIP and betaine carboxylate. The CIP-CB conjugate exhibits unique self-assembly behavior, forming stable micellar nanostructures with pH-responsive charge reversal properties (Fig. 14).¹³² Then, 5,10,15,20-tetraphenylporphyrin PS (TPP) was loaded into CIP-CBMs micelles to form TPP@CIP-CBMs. At infection sites, acidic pH induces betaine protonation, creating cationic TPP@CIP-CBMs that target bacterial cells and enhance the biofilm penetration. Concurrently, light-activated ROS production disrupts biofilms while pathogen-secreted lipases hydrolyze micelles for controlled CIP release, enabling double-mode antimicrobial action. In another study, Xiang et al. synthesized a ZIF/PGA-C/M nanocomposite by sequentially loading CIP and MB into ZIF nanoparticles, followed by surface coating with poly-γ-glutamic acid (PGA) using ethylene glycol dimethacrylate (EGDMA) as a crosslinker.¹³³ By combining ZIF's pH sensitivity with EGDMA's esterase responsiveness, ZIF/PGA-C/M achieves infection-site-specific drug release through dual pH/lipase activation, optimizing local drug bioavailability while minimizing systemic exposure. Under acidic conditions (pH 5.5) and in the presence of lipase, ZIF/PGA-C/M efficiently releases CIP (C) and methylene blue (MB, M), with release rates of 99.4% and 76.0%, respectively. Moreover, MB generates ¹O₂ under near-infrared light, further improving the antibacterial effect. Experimental results show that ZIF/PGA-C/M exhibits excellent inhibition of MRSA, demonstrating strong antibacterial activity both in planktonic and biofilm states. In a mouse skin infection model, the treatment group receiving ZIF/PGA-C/M combined with near-infrared light showed the fastest wound healing, with no significant side effects observed.

Fig. 14 Schematic illustration of the preparation and its photodynamic antibacterial process of TPP@CIP-CBMs. Reproduced with permission from ref. 132. Copyright 2023 Elsevier.

4.3.2. pH/ATP-dual responsive platforms for smart microenvironment recognition and synergistic therapy. The MXene/ZIF-90@ICG nanospray developed by Ding et al. utilizes amide-bond crosslinking to integrate ICG-loaded ZIF-90 with MXene nanosheets, creating a pH/ATP dual-responsive system for smart infection microenvironment recognition and adaptive therapy (Fig. 15).¹³⁴ Under acidic conditions (pH 5.5) or high ATP concentrations, the ZIF-90 framework disintegrates, triggering the controlled release of antibacterial agents such as MXene, ICG, and Zn²⁺. MXene/ZIF-90@ICG enables precision antibacterial therapy through NIR-activated photothermal (69 °C) and photodynamic therapies, with ZIF-90 providing controlled release capabilities for enhanced targeting efficacy. Combined with the inherent antibacterial activity of Zn²⁺, a triple synergy mechanism involving PDT, photothermal therapy (PTT), and metal ions is formed, achieving an inactivation rate of 99.35% for Gram-positive bacteria (e.g., S. aureus) and 98.96% for Gram-negative bacteria (e.g., E. coli). Notably, the dual-responsive mechanism not only reduces potential damage to normal tissues but also accelerates the release of antibacterial agents and ROS generation in real-time through NIR, enabling dynamic regulation of the treatment process. In in vivo experiments, the nanospray demonstrated excellent biocompatibility, effectively promoting the healing of infected wounds, and allowed for real-time monitoring of ICG release via fluorescence imaging, providing new insights for the design and application of intelligent antibacterial systems.

Fig. 15 Schematic illustration of the preparation of MXene/ZIF-90@ICG and its photodynamic antibacterial application. Reproduced with permission from ref. 134. Copyright 2024 American Chemical Society.

4.3.3. pH/H₂O₂-dual responsive platforms for enhanced photodynamic activity in infectious microenvironments. Zhao et al. developed a pH/H₂O₂ dual-responsive nanoplatform (TP nanoparticles),¹³⁵ which integrates H₂O₂-sensitive phenylboronic ester-based copolymers POEGMA-b-PBMA (i.e., poly (oligo (ethylene glycol) methyl ether methacrylate)-b-poly benzyl methacrylate) with an acidity-induced charge-reversal photosensitizer, 5,10,15,20-tetra-{4-[3-(N,N-dimethyl-ammonio) propoxy]phenyl} porphyrin (TAPP) to create a precise antibacterial system targeting infectious microenvironments. The nanoparticles disassemble under the elevated levels of H₂O₂ and acidic conditions typical of infection sites, releasing TAPP. Protonation of TAPP significantly enhances its hydrophilicity and reduces aggregation, thereby improving its photodynamic effect. Experimental results show that under 650 nm laser irradiation, the singlet oxygen production rate of protonated TAPP increased by nearly 80% compared to neutral conditions, significantly enhancing bactericidal activity against S. aureus and E. coli. The dual-responsive mechanism not only enables the specific release of the drug at the lesion site but also enhances the electrostatic interaction between the photosensitizer and the bacterial cell wall through acid-induced charge reversal, further optimizing targeting. Furthermore, TP nanoparticles exhibited robust biofilm eradication efficacy in both in vitro and in vivo models. These nanoparticles effectively degrade the biofilm extracellular matrix and achieve deep penetration into bacterial aggregates, overcoming the intrinsic limitations of conventional antibiotics in biofilm penetration. The excellent biocompatibility of TP nanoparticles highlights strong translational potential for chronic wound management, while offering valuable design principles for developing multi-stimuli-responsive antimicrobial platforms.

5. Conclusions and future directions

This review comprehensively examines SRPT platforms for bacterial infections, encompassing: (1) fundamental principles of PDT, (2) stimulus-responsive activation mechanisms, and (3) recent advances in the development of SRPT platforms. SRPT platforms exploit unique pathophysiological features of infection sites (e.g., acidic pH and overexpressed enzymes) as biological triggers. These intelligent systems remain inactive in healthy tissues, activating only upon encountering disease-specific physicochemical factors to minimize off-target effects. While first-generation PSs such as porphyrin derivatives have achieved clinical translation, most advanced SRPT platforms remain in preclinical development due to persistent technical challenges.

Current physicochemical factor selection faces specificity limitations, as targeted signals like hypoxia or redox gradients may transiently appear in healthy tissues, potentially causing false activation and collateral damage. Future designs should incorporate dual turn-on systems requiring concurrent detection of multiple physicochemical factors to ensure pathogen-specific activation. In addition, most existing PSs are limited to visible light absorption (400–700 nm), restricting treatment to superficial infections.¹³⁶ Developing PSs with near-infrared absorption (700–900 nm) could enable deeper tissue penetration, potentially expanding applications to orthopedic implants or pulmonary infections.¹³⁷

Regarding bacterial selectivity, SRPT platforms achieve targeted killing of pathogens through two primary mechanisms: (1) activation confined to infection microenvironments (e.g., acidic pH, hypoxia, and redox imbalance), which are distinct from healthy tissues hosting commensal bacteria; (2) exploitation of pathogen-specific biomarkers (e.g., β-lactamase in MRSA, PaAP in P. aeruginosa), ensuring that therapeutic activity is triggered predominantly by virulence factors absent in beneficial bacteria. Future designs may integrate bacterial species-specific ligands (e.g., antibodies and aptamers) to further enhance precision.

Despite the therapeutic potential of PSs, significant challenges remain regarding their chemical stability, particularly concerning aggregation in biological environments and susceptibility to photobleaching. These limitations are compounded by interpatient variability in physicochemical factors, highlighting the need for personalized SRPT approaches integrated with real-time imaging. Notably, combinatorial strategies integrating SRPT platforms with synergistic antibacterial modalities have demonstrated markedly improved efficacy against persistent infections in recent studies.¹³⁸

As a targeted therapeutic modality, SRPT platforms show considerable promise for addressing drug-resistant bacterial infections. Future research efforts are expected to yield significant advancements that will facilitate the translation of this technology from preclinical studies to clinical applications, ultimately expanding treatment options for resistant pathogens.

Conflicts of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

All the data will be made available on reviewers’ request.

Acknowledgements

This work was supported by the Excellent Youth Foundation of Jiangxi Scientific Committee (No. 20232ACB213012), the Jiangxi Talent Program (No. DHSQT32022005), and the National Science Foundation of Jiangxi province of China (No. 20242BAB25236).

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