Recent advances in NIR-II emitting nanomaterials: design and biomedical applications of lanthanide complexes and functionalized mesoporous silica nanoparticles (MSNs)

Abstract

The second near-infrared (NIR-II, 1000–1700 nm) region has gained significant attention due to its superior tissue penetration depth, reduced photon scattering, and minimal autofluorescence compared to the first near-infrared (NIR-I, 700–900 nm) window. These advantages make NIR-II an ideal spectral range for bioimaging, photothermal therapy (PTT), and photodynamic therapy (PDT). Various nanomaterials, including metal-based complexes, organic dyes, and carbon-based materials, have been engineered to serve as efficient NIR-II agents for enhanced biomedical applications. Among these, mesoporous silica nanoparticles (MSNs) have emerged as versatile nanoplatforms due to their tunable porosity, high surface area, and biocompatibility. MSNs can be modified with different functional materials, such as luminescent coordination complexes, organic dyes, and metal nanoclusters, to optimize photothermal conversion efficiency and imaging capabilities. Their ability to encapsulate therapeutic agents further enables controlled drug delivery and combinational cancer therapies. Additionally, hybrid MSN systems incorporating nanocarbon materials (e.g., fullerenes, carbon nanotubes) and metal nanoparticles have been explored to enhance stability and bioavailability. Despite their promising potential, challenges such as long-term biocompatibility, clearance mechanisms, and precise targeting remain key hurdles in clinical translation. Future research should focus on overcoming these limitations by developing next-generation MSN-based nanocomposites, such as MSN–graphene oxide, MSN–fullerenes, MSN–carbon nanotubes, MSN-quantum dots, and MSN–metal nanoparticles. These advancements will pave the way for improved therapeutic efficacy and broader biomedical applications.

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1. Introduction

The second near-infrared (NIR-II, 1000–1700 nm) region, extending beyond the first near-infrared (NIR-I, 700–900 nm) window, has emerged as a promising field due to its ability to achieve significant penetration depths and low background noise in biological tissues.¹ This unique optical window has driven numerous advancements in biomedical applications.² Light-tissue interactions, such as reflection, scattering, absorption, and autofluorescence, play a critical role in bio-optical technologies (Fig. 1).³ Scattering is a major contributor to high background noise, reducing penetration depth by dissipating energy. However, in the NIR-II region, scattering is substantially reduced compared to visible and NIR-I wavelengths, as the scattering effect decreases with increasing wavelength across most biological tissues.^4–6 This reduction leads to higher signal-to-noise ratios (SNRs) and improved penetration. Autofluorescence, caused by natural fluorophores within tissues, also diminishes significantly with longer wavelengths, becoming nearly negligible above 1500 nm.^7,8 This low autofluorescence further enhances the SNR in the NIR-II region. Additionally, the lower photon energy at longer wavelengths allows for a higher maximum permissible exposure (MPE) to biological tissues, enabling the use of greater laser power densities in the NIR-II range compared to NIR-I. However, care must be taken to avoid water absorption peaks near 1450 nm.⁹ With its ability to deliver high resolution, deep tissue penetration (exceeding 1 cm), and superior SNRs, NIR-II fluorescence imaging has garnered substantial interest as a tool for developing advanced bio-optical solutions.

Fig. 1 (a) Schematic illustration of light-tissue interaction; (b) schematic illustration of the design elements and bio-optical applications of NIR-II emitting LnNPs. Reproduced with permission from ref. 3. © 2020 Elsevier. All rights reserved.

NIR-II probes have gained significant attention due to their remarkable properties and potential applications in bioimaging, sensing, and therapeutic fields.^10–12 These probes are primarily categorized into five groups: single-walled carbon nanotubes (SWCNTs),^13,14 conjugated polymers,¹⁵ organic dyes,¹⁶ quantum dots (QDs),¹⁷ and lanthanide (Ln³⁺)-containing probes.^18,19 Despite their usefulness, each of these categories presents limitations that hinder their broader application. For instance, SWCNTs exhibit broadband emissions exceeding 300 nm but are limited by low photoluminescence (PL) quantum yields, typically ranging between 0.1% and 0.4%.²⁰ Similarly, QDs face challenges related to high toxicity, while both conjugated polymers and organic dyes demonstrate poor solubility in aqueous solutions and a susceptibility to photobleaching, making them less practical for long-term biological applications.^21,22

In comparison to these conventional probes, Ln³⁺-containing nanoparticles (NPs) offer unique advantages due to their intrinsic electronic configurations and robust optical properties. The electron configuration of Ln³⁺ ions, denoted as 4fⁿ5s²5p⁶ (n = 0–14), enables them to emit across a wide spectrum, from ultraviolet (UV) to visible and near-infrared (NIR) wavelengths. Specific lanthanide ions such as Yb³⁺, Tm³⁺, Er³⁺, Ho³⁺, Dy³⁺, Sm³⁺, Nd³⁺, and Pr³⁺ are particularly effective in generating NIR-II emissions.^23,24 This capability arises from their rich energy levels and the shielding effect of their 4f orbitals by the outer 5s and 5p orbitals, which minimizes interactions with the surrounding environment. Consequently, Ln³⁺ ions exhibit sharp, tunable emissions with high photostability, making them highly suitable for bioimaging applications.^25–28

An extension of this technology is the development of lanthanide metal–organic frameworks (Ln-MOFs), which combine the exceptional fluorescence properties of lanthanides with the intrinsic advantages of metal–organic frameworks (MOFs).²⁹ Ln-MOFs are crystalline materials created through the self-assembly of trivalent lanthanide ions and organic ligands, resulting in structures with high porosity, tunability, and surface modifiability.^30,31 These frameworks possess excellent biocompatibility, making them suitable for a variety of applications, including catalysis, gas separation, chemical sensing, bioimaging, and drug delivery.^32,33 The unique “antenna effect” between lanthanides and ligands enhances their fluorescence intensity, stability, and quantum yields while providing large Stokes shifts exceeding 150 nm.³⁴ For visible-light applications, Tb-MOFs and Eu-MOFs are particularly notable, with research demonstrating their utility in sensing and imaging.^35–37 For instance, Tb-MOFs have been used to detect Pb²⁺ ions with a detection limit as low as 10⁻⁷ M, while Eu-MOFs have shown potential for cancer diagnostics by combining fluorescence imaging and magnetic resonance imaging (MRI) capabilities.^38–40 In the NIR-II region, Yb-MOFs show great promise, such as “turn-on” sensors for gossypol with 25 μg mL⁻¹ sensitivity.⁴¹ These materials combine structural tunability, large surface area, and stable emissions, offering a unique blend of organic–inorganic characteristics highly suitable for both in vitro and in vivo imaging.^42,43

Recent advancements in multifunctional nanotheranostic platforms have demonstrated the promising synergistic potential of combining photothermal therapy (PTT) with other modalities such as nitric oxide (NO)-mediated gas therapy (GT), chemotherapy, photodynamic therapy (PDT), chemodynamic therapy (CDT), and immunotherapy for enhanced cancer treatment outcomes. Dual-modal systems incorporating NO donors activated by diverse stimuli, including light, ultrasound, ROS, and glutathione, enable precise NO release and reduced systemic toxicity, thereby improving therapeutic efficacy.⁴⁴ Platforms such as gadolinium-doped carbon dots (aPD-L1@GdCDs) integrate immune checkpoint blockade with mild PTT/PDT to convert immunologically cold tumors into hot ones, significantly enhancing antitumor immune responses.⁴⁵ Europium-grafted polydopamine nanoparticles (FEDA) and europium-complexed oxidative dopamine (ECOD) nanoparticles offer dual-modality imaging (CT/photoluminescence) and effective PTT with high tumor-targeting efficiency.^46,47 Manganese-based hollow nanostructures further serve as multi-agent delivery systems supporting PTT, PDT, and CDT while enhancing MRI contrast and Fenton-like catalytic therapy.⁴⁸ Similarly, BSA–Ag:CuS and GCGLS nanoparticles provide stable, biocompatible platforms for synergistic CDT/PTT and imaging-guided PTT, respectively.^49,50 MnO₂/IR780-based nanocomposites improve IR780 limitations, support oxygen generation, and enable MRI-guided PDT/PTT.⁵¹ Other combinatorial systems, such as MnO₂@NH₂-MIL101(Fe)@Ce6-F127 for CDT/PDT and GBD-Fe for CT/CDT/PTT, enhance therapeutic depth and precision through ROS generation and TME modulation.^52,53 Notably, NIR-II responsive hollow nanoplatforms exhibit exceptional capabilities in multi-agent delivery, deep-tissue PTT, and multimodal imaging (PAI/MRI), positioning them at the forefront of future translational cancer nanomedicine despite challenges in scalability, biosafety, and clinical translation.⁵⁴

Alongside Ln³⁺-incorporated metal–organic frameworks (Ln-MOFs) offer a unique combination of structural precision, spectral tunability, and superior optical performance, setting them apart from conventional nanomaterials. Unlike carbon nanotubes and quantum dots, which suffer from poor biocompatibility or intrinsic toxicity, Ln-MOFs exhibit excellent biocompatibility, low cytotoxicity, and enhanced biodegradability. Compared to organic dyes and conjugated polymers that face issues with photobleaching and aqueous solubility, Ln-MOFs demonstrate robust photostability and sustained emission under biological conditions.^{42–45,55,56}

The novelty of this system lies in the modular design of the MOF architecture that allows precise control over the lanthanide environment, thereby tuning the emission lifetimes, quantum yields, and energy transfer pathways. This structured design enables high-resolution, deep-tissue imaging with minimal background interference—characteristics highly desirable for next-generation diagnostic tools. Moreover, the dual advantages of high porosity and large surface area in MOFs enable multifunctionality, including drug loading and biomolecule conjugation, thereby extending their application beyond imaging to theranostics. However, despite their potential, biological imaging systems utilizing NIR-II MOF materials remain underexplored, particularly for NIR-II bioimaging applications.^55–57

In parallel, functionalized mesoporous silica nanoparticles (MSNs) also represent a powerful and complementary platform for NIR-II biomedical applications. MSNs offer exceptional surface area, tunable pore size, and excellent biocompatibility, allowing them to efficiently encapsulate and stabilize NIR-II fluorophores, thus improving photostability, quantum yield, and resistance to photobleaching. Their easily modifiable surface chemistry enables targeted delivery and the incorporation of stimuli-responsive elements, such as pH or enzyme-sensitive gatekeepers, allowing for controlled drug release in biological environments. Unlike rigid systems such as carbon nanotubes or quantum dots, MSNs support the integration of therapeutic agents and multiple imaging modalities within a single construct. Their biodegradability and favorable clearance properties further enhance their potential for clinical translation. Together with Ln-MOFs, functionalized MSNs offer complementary strengths that address many of the limitations faced by conventional NIR-II nanoprobes, paving the way for the development of next-generation multifunctional imaging and theranostic platforms.^57–59

Ln³⁺-based nanoparticles represent a new generation of NIR-II probes, offering immense potential for multiplexed sensing, time-gated detection, and high-resolution imaging.^55–57 Recent efforts have focused on optimizing their optical performance through various strategies, including tuning excitation and emission wavelengths, manipulating PL lifetimes, and enhancing PL intensities. (Fig. 2).^58–60 Surface modification approaches, such as inorganic shell coatings, organic polymer integration, and conjugation with biofunctional agents, have further enhanced their utility.⁶¹ These modifications improve the stability, biocompatibility, and functionality of Ln³⁺-containing nanoparticles, paving the way for their integration into advanced bioimaging systems.⁶²

Fig. 2 Summary of Ln³⁺-containing NIR-II luminescent nanoprobes from fundamentals to design strategies.

Despite the progress made, most existing reviews emphasize the chemical and application aspects of Ln³⁺-containing NIR-II nanoprobes while overlooking their fundamental electronic structures and optical design principles. Addressing this gap is crucial, particularly given the significant advancements in this field over recent years. Future research should focus on a deeper understanding of their localized electronic structures, novel design strategies, and innovative approaches to optimize their optical properties and surface modifications. By addressing these areas, Ln³⁺-based NIR-II nanoprobes have the potential to revolutionize bioimaging, sensing, and theranostics, offering high-resolution imaging and advanced diagnostic and therapeutic solutions.

2. Design of NIR emitting lanthanide materials

2.1 Synthesis method for Ln-MOF materials

Lanthanide metal–organic frameworks (Ln-MOFs) are a fascinating class of porous materials that combine lanthanide ions with organic linkers to form crystalline, highly ordered networks with tunable structures and multifunctional properties.⁶³ These frameworks find applications in sensing, catalysis, gas storage, drug delivery, and luminescence, and their synthesis typically employs a bottom-up approach where metal nodes and organic linkers react under specific conditions.⁶⁴ Synthesis strategies for Ln-MOFs involve using directional and rigid aromatic ligands, especially carboxylate groups, which facilitate robust and thermally stable frameworks suited to the oxophilic nature of lanthanide ions (Fig. 3).³⁰ Despite various methodologies enabling the formation of complex, highly ordered, and reproducible structures with desired crystallinity, challenges remain in achieving thermally stable, porous networks. Advances in these strategies, enhance the performance of MOF materials for diverse applications while addressing the inherent difficulties of each approach.⁶⁵

Fig. 3 Different synthesis procedures of Ln-MOF.

2.1.1 Solvothermal synthesis method. Solvothermal methods are widely used for synthesizing conventional and lanthanide-based MOFs (Ln-MOFs). These processes involve heating metal salts and organic ligands in a closed system under controlled conditions to achieve highly crystalline, porous structures.⁶⁶ Reaction temperature plays a key role, with solvothermal conditions operating below the solvent's boiling point and non-solvothermal conditions exceeding it. Slow, reversible coordination reactions between metal ions and ligands ensure structural precision, while dilute solutions and prolonged reaction times promote high-quality crystal growth.⁶⁷ Byproduct management is critical; for example, HCl from metal chlorides can hinder growth, while milder byproducts from acetylacetonates support better crystallization. In cases of rapid bond formation, modulators are used to slow reactions, enhancing crystallization while introducing beneficial structural defects.^68,69 These defects improve properties like surface area, pore size, and catalytic activity. Careful tuning of reaction parameters ensures MOFs with desired morphology, crystallinity, and functionality for diverse applications.⁷⁰

Yaghi et al. were among the first to explore the solvothermal synthesis of lanthanide metal–organic frameworks (Ln-MOFs) Fig. 4. They developed a microporous Tb-BDC framework by dissolving Tb(III) nitrate pentahydrate and 1,4-benzenedicarboxylic acid (H₂BDC) in methanol/DMF, followed by mild heating in a sealed vial.⁵⁵ Thermogravimetric analysis (TG) revealed thermal stability up to 320 °C, with weight loss corresponding to 1.97 DMF molecules per formula unit of Tb₂(BDC)₃. Further refinement using a solvothermal process at 140 °C for 12 hours converted hydrated Tb₂(BDC)₃·(H₂O)₄ into a stable microporous Tb₂(BDC)₃ system with enhanced thermal stability up to 450 °C. Other ligand systems have further advanced Ln-MOF properties. Liu et al. synthesized Eu-BTC-based MOFs using 1,3,5-benzenetricarboxylic acid (H₃BTC) and Eu(III) nitrate hydrate in a water–DMF solvent mixture. The size of Eu-BTC particles was tunable by adjusting the H₂O/DMF ratio, transitioning from larger crystals (35 ± 6 μm) to smaller microcrystals (10 ± 5 μm) as the solvent ratio varied. Water acted as both a molecular coordinator and solubility adjustor, enabling size control. These Eu-MOFs exhibited thermal stability up to 600 °C, with significant weight loss above this temperature due to linker decomposition.^71,72

Fig. 4 Tb-BDC chains shown perpendicular to the c axis. © 1999 Wiley. All rights reserved. Reproduced with permission from ref. 71. © 1999 Wiley. All rights reserved.

2.1.2 Microwave-assisted large-scale synthesis of Ln-MOFs. Bag et al. developed a rapid and scalable microwave-assisted solvothermal approach for synthesizing a series of isostructural microporous lanthanide metal–organic frameworks (Ln-MOFs) with the general formula [Ln(TTTPC)(NO₂)₂(Cl)]·(H₂O)₁₀, where Ln represents lanthanides such as La, Ce, Pr, Nd, Eu, Tb, Dy, Ho, and Yb. The synthesis of [La(TTTPC)(O)₂(NO₂)₂(Cl)]·(H₂O)₁₀ was achieved by combining La(NO₃)₃·6H₂O (0.0471 mmol, 20.45 mg), H₃TTTPC (0.0157 mmol, 10 mg), and a mixed solvent (1 mL, H₂O/EtOH = 1 : 1) in a 2 mL microwave tube. The mixture was subjected to microwave heating under autogenous pressure at 85 °C for 5 minutes, followed by natural cooling to room temperature (Fig. 5).⁷³

Fig. 5 (a) The coordination environment of the central metal ion. (b) Dodecahedral geometry of the central metal ion. (c) Two adjacent Ce³⁺ ions are bridged by four carboxylate groups from four TTTPC ligands to yield a paddel-whele structure. Reproduced with permission from ref. 73. © 2015 Royal Society of Chemistry. All rights reserved.

Notably, the same compound could be synthesized using a conventional solvothermal method at 85 °C over 2 days, yielding a comparable product. Colorless crystals suitable for single-crystal X-ray diffraction analysis were obtained through filtration, multiple washings with the H₂O/EtOH (1 : 1) solvent mixture, and air drying at ambient temperature. The resulting compound demonstrated stability in air and was insoluble in common organic solvents such as methanol, ethanol, acetonitrile, acetone, dimethyl sulfoxide (DMSO), and N,N-dimethylformamide (DMF). This method highlights the potential of microwave-assisted techniques for efficient and scalable synthesis of Ln-MOFs with robust chemical and structural properties.^74–76

2.1.3 Hydrothermal synthesis of lanthanide sulfate–oxalates. Wang et al. present a detailed synthesis and structural characterization of lanthanide sulfate–oxalate frameworks with the formula [NH₄][Ln(H₂O)(SO₄)(C₂O₄)]_n, where Ln = Y, La, Sm.⁷⁷ These compounds were synthesized using hydrothermal methods to develop three-dimensional open-framework structures with potential applications in luminescence and magnetism. The synthesis began with the preparation of a precursor solution. Lanthanide nitrate salts (Ln(NO₃)₃·6H₂O) were dissolved in deionized water, while oxalic acid (H₂C₂O₄) and ammonium sulfate ((NH₄)₂SO₄) were mixed in a separate solution to create an acidic medium. These solutions were combined under continuous stirring to ensure homogeneity. The mixture was then transferred to a Teflon-lined autoclave and heated at 180 °C for 72 hours. This hydrothermal process provided the high-pressure and high-temperature environment necessary for the crystallization of the lanthanide sulfate–oxalate frameworks. After cooling naturally to room temperature, the crystalline product was collected via vacuum filtration, washed thoroughly with deionized water, and dried at 60 °C under vacuum for 12 hours (Fig. 6).

Fig. 6 (a) The asymmetric unit of compound I. Color code: Y, azure; S, yellow; N, dark blue; C, green; O, red; and H, gray. Structures of 1D zigzag chain formed by Y and oxalate group (b), [Y(SO₄)(H₂O)] inorganic chain (c). Reproduced with permission from ref. 77. © 2010 Elsevier. All rights reserved.

The resulting compounds crystallized in the monoclinic system with the space group P2₁/n. Their structures featured lanthanide centers coordinated with sulfate (SO₄²⁻) and oxalate (C₂O₄²⁻) ligands, forming intricate three-dimensional frameworks. Ammonium cations (NH⁴⁺) occupied interstitial spaces, contributing to the stability of the structure. The frameworks contained 12-membered ring channels aligned along the a- and b-axes, which endowed them with their characteristic open-framework architecture.

These materials demonstrated excellent thermal stability up to 300 °C, as confirmed by thermogravimetric analysis, and exhibited luminescence properties characteristic of lanthanide ions, making them suitable for optical applications. The study highlights the potential of these frameworks in developing luminescent devices and magnetic materials. Future work could explore the synthesis of similar materials with different lanthanides to expand their functional applications in catalysis, gas storage, and energy systems. This synthesis procedure exemplifies the meticulous conditions and coordination chemistry required to achieve such advanced materials.

2.1.4 Precipitation method for Ln-MOF synthesis. The precipitation method is one of the simplest and most efficient strategies for synthesizing Ln-MOF systems.⁷⁸ Compared to solvothermal methods, it offers advantages such as high product yield, low energy requirements, and rapid synthesis. In this approach, precipitation is triggered by using a poor solvent, typically through one of two methods: (1) dissolving the metal ions and organic linkers in separate solvents and then mixing them to induce MOF formation, or (2) dissolving the precursors in one solvent and transferring the solution to another solvent that promotes precipitation.⁷⁹ By adjusting precursor concentration, solution pH, and the choice of precipitating solvent, crystalline Ln-MOFs can be obtained.

This method has been employed to synthesize various Ln-MOFs. The first nanoscale Ln-MOF, reported in 2008, utilized Tb(III) ions and the c,c,t-(diamminedichlorodisuccinato)Pt(IV) (DSCP) linker, producing an amorphous coordination polymer, as confirmed by PXRD analysis.^80,81

Zhang et al. synthesized a Tb(III)-based MOF, Tb(1,3,5-BTC)(H₂O)·3H₂O, by mixing and vigorously shaking ethanol–water solutions of 1,3,5-H₃BTC and Tb(NO₃)₃ at room temperature. The resulting one-dimensional, sheaf-like nanostructures were attributed to a splitting growth mechanism and demonstrated utility as sensors for metal ions and acetone (Fig. 7).^82,83

Fig. 7 The asymmetric unit (a), coordination modes of the carboxylate groups (b), 1D helical structure along the a axis (c), perspective view of the packing along the c axis of the Tb(1,3,5-BTC)(H₂O)·3H₂O (d). All of the figures were drawn using the CIF file of MOF-76 or reported Eu(1,3,5-BTC)(H₂O) single crystal. The hydrogen atoms were omitted for clarity. Tb green (shown as polyhedra), O red, C gray. Reproduced with permission from ref. 82. © 2010 Royal Society of Chemistry. All rights reserved.

Liu et al. extended this approach to nano- and micro-sized Ln-MOF coordination polymers, Ln(1,3,5-BTC)(H₂O)₆ (Ln = Eu³⁺, La³⁺, Ce³⁺), by shaking aqueous Ln(NO₃)₃ solutions with water–ethanol solutions of 1,3,5-H₃BTC. By modifying synthesis parameters such as precursor concentration, reactant molar ratios, surfactant use, and solvents, they achieved novel 3D flower-like superstructures. Furthermore, co-doping with Tb³⁺ and Eu³⁺ enabled tunable photoluminescence, producing emissions across red, orange, yellow, green-yellow, and green spectrums, demonstrating the versatility of the precipitation method in designing functional Ln-MOF materials.⁸⁴ Comparative study of the MOF synthetic procedure discussed in Table 1.

Table 1 Comparative summary of Ln-MOF synthesis methods

Synthesis method	Advantages	Limitations	Scalability
Solvothermal synthesis	Highly crystalline MOFs; tunable reaction conditions; well-established	Time-consuming; may need modulators; sensitive to by-products	Moderate (requires large reactors & longer time)
Microwave-assisted synthesis	Rapid synthesis; energy-efficient; scalable to large batches	Requires microwave system; risk of non-uniform heating in scale-up	High (suitable for high-throughput production)
Hydrothermal synthesis	Good for forming 3D open frameworks; allows structural diversity	Needs high temp & pressure; long duration; autoclave required	Moderate (scalable but requires large autoclave systems)
Precipitation method	Simple setup, low energy use; high product yield	Limited structural control; may form amorphous or lower-quality crystals	High (simple solvent setup supports scale-up)

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2.2 Design of efficient Ln doped nanoparticles (LnNPs)

2.2.1 Constitution and luminescent mechanism of NIR emitting LnNPs. Lanthanide nanoparticles (LnNPs) are generally composed of host matrices, sensitizers, and activators. The host matrix plays a crucial role in ensuring optical transparency and facilitating efficient luminescence processes.⁸⁵ Both the sensitizers and activators are typically lanthanide ions in the +3-oxidation state. Within the crystal field provided by the host matrix, the excited states of these ions split into distinct energy levels, forming a ladder-like structure. Upon laser irradiation at appropriate wavelengths, the sensitizers are excited, and they subsequently transfer their energy to the activators.³ This energy transfer excites the activators, which then emit luminescence as their excited electrons return to the ground state. Table 1 outlines common compositions of LnNPs that emit in the NIR-II region, reflecting recent advancements in this field. There are three distinct mechanisms responsible for NIR emission in LnNPs:⁸⁶

(a) Upconversion process: Er³⁺ serves as the sensitizer, transferring energy to activators like Nd³⁺, Ho³⁺, or Tm³⁺, resulting in NIR luminescence.

(b) Stokes emissions: this occurs when activators emit light after receiving energy from sensitizers such as Yb³⁺ or Nd³⁺.

(c) Intrinsic emissions: NIR light is directly emitted by Nd³⁺ or Er³⁺ ions following their excitation.

NIR-emitting LnNPs have found applications in imaging, particularly for light-to-heat and heat-to-temperature conversions, within single or hybrid nanoparticle-based devices in the NIR-II spectrum.⁸⁷ These techniques are invaluable for characterizing biological tissues, as NIR-II spectroscopy and imaging reveal significantly enhanced absorption features for tissue components like water, lipids, and collagen compared to the Vis-NIR range. Moreover, the scattering coefficient decreases following a power-law decay from Vis-NIR to NIR-II, allowing for deeper light penetration and heightened sensitivity.⁸⁸ This sensitivity aids in detecting variations in constituent concentrations linked to health conditions, such as atherosclerosis and breast cancer.⁸⁹

NIR-II luminescence is particularly advantageous for imaging applications, offering benefits over fiber-probe-based methods. It enables non-contact imaging of in vivo or ex vivo tissues over areas spanning several centimeters in both x- and y-dimensions. This capability is especially valuable in fluorescence-guided surgery, providing higher-resolution imaging of subsurface structures. However, protocols to minimize background noise, as with other fluorescence techniques, are critical for successful surgical applications.⁹⁰ A major limitation of LnNPs in NIR-II imaging is their low quantum efficiency, often below 3%. Recent advancements have focused on developing novel compositions to enhance their optical performance, addressing this challenge and broadening their potential in biomedical imaging.⁹¹

To enhance the optical performance of NIR-II emitting LnNPs, a core/shell structure is frequently employed (Fig. 8). The core, which typically contains both sensitizers and activators, serves as the primary source of NIR-II emissions. Surrounding the core, the shell can either be inert or active and in some designs, multiple-layered shells are constructed. Inert shells, made from optically inactive materials such as NaYF₄ or NaLuF₄, encapsulate the core and effectively passivate surface defects, minimizing surface-related quenching.⁹² Alternatively, active shells incorporate sensitizers and/or activators. These shells not only reduce surface defects but also facilitate energy transfer between the dopants in the core and across different shells, thereby enhancing the optical tunability of LnNPs.⁹³

Fig. 8 (a) Schematic illustration of the core/shell structure; (b) simplified energy transfer pathways for NIR-II emissions of Ln³⁺ (Ln¼ Ho, Pr, Er, Tm) using Yb³⁺ as the sensitizer. The dashed curve indicates the energy transfer from Yb³⁺ to Tm³⁺ and the simultaneous two-photon ESA process of Tm³⁺; (c) simplified energy-level diagrams depicting the energy transfer involved in a-ErNPs on 980 nm excitation. Reproduced with permission. (d) Simplified energy transfer pathways for NIR-II emissions of Er³⁺ using Nd³⁺ as the sensitizer. (e) Simplified energy transfer pathways for NIR-II emissions of Ln³⁺ (Ln¼ Nd, Ho, Tm) using Er³⁺ as the sensitizer and the intrinsic NIR-II emissions of (f) Nd³⁺ and (g) Er³⁺; (h) simplified energy transfer pathways for the NIR-II emissions of Er³⁺ using Tm³⁺ as the sensitizer. Reproduced with permission from ref. 3. © 2020 Elsevier. All rights reserved.

Lanthanide nanoparticles (LnNPs) are extensively studied for their NIR-II emission properties, with their optical performance often enhanced through innovative designs and materials (Fig. 8). Yb³⁺ is commonly used as a sensitizer for Ln³⁺ activators like Ho³⁺, Pr³⁺, Er³⁺, and Tm³⁺, producing emissions at 1155 nm, 1289 nm, 1525 nm, and 1475 nm, respectively. When Yb³⁺ absorbs 980 nm illumination, energy is transferred to Ln³⁺ activators, resulting in NIR-II luminescence. Recent studies show that doping Yb³⁺–Er³⁺ pairs with Ce³⁺ and Zn²⁺ significantly boosts brightness and suppresses upconversion transitions by facilitating efficient energy relaxation.⁶¹ Additionally, Zn²⁺ doping reduces crystal field symmetry, enhancing both brightness and lifetime.

While Yb³⁺–Tm³⁺ and Yb³⁺–Pr³⁺ pairs show limited NIR-II emissions, Nd³⁺ and Er³⁺ serve as sensitizers and activators in some systems. Nd³⁺ effectively transfers energy to Yb³⁺, which excites Er³⁺, yielding strong emissions at 1525 nm. Moreover, Er³⁺ can directly sensitize activators like Nd³⁺, Ho³⁺, and Tm³⁺via energy transfer, while both Nd³⁺ and Er³⁺ intrinsically emit in the NIR-II range under specific excitations.^23,94,95

Optimizing sensitizer and activator concentrations is crucial, as low concentrations result in weak emissions, and high concentrations may cause quenching. Recent findings suggest surface defects, rather than cross-relaxation among dopants, are the primary cause of luminescence quenching. Core/shell structures, such as NaY(Er)F₄@NaLuF₄, mitigate this effect, enabling efficient emissions even in heavily doped nanoparticles.⁹²

Tm³⁺ has also emerged as a promising sensitizer, exhibiting strong absorption and energy transfer to Er³⁺, producing intense NIR-II emissions at 1525 nm in core/shell nanoparticles. Controlled Tm³⁺ doping allows tunable lifetimes and applications in fluorescence-lifetime imaging.⁹⁶

Fluoride-based host materials, such as NaYF₄ and NaGdF₄, are preferred due to low phonon energy and structural versatility. While hexagonal (β-phase) hosts are widely used for reduced nonradiative relaxation, recent research shows cubic (α-phase) LnNPs can deliver brighter NIR-II emissions due to phonon-assisted relaxation processes. Zn doping further amplifies down-conversion luminescence, achieving lifetimes up to 7.0 ms.⁹⁷

Sulfides, like CaS, are gaining attention as alternative hosts. Co-doping with Ce³⁺/Er³⁺ or Ce³⁺/Nd³⁺ yields high fluorescence efficiency under blue LED excitation, offering quantum yields of 9.3% and 7.7%, respectively. This novel approach enables applications as responsive biosensors for bioassays, highlighting the potential of LnNPs in advanced optical technologies.

An example of advanced multi-layered LnNPs is the structure β-NaGdF₄@Na(Gd,Yb)F₄:Er@NaYF₄:Yb@NaNdF₄:Yb, which has been utilized as a probe for in vivo imaging. When excited at 800 nm—within the “biological transparency window” characterized by minimal water absorption and heat generation—these nanoparticles emit in the NIR-II region, specifically at 1525 nm. This excitation wavelength is ideal for minimizing impact on biological tissues.^98,99

The nanoparticles were made water-dispersible by coating them with phospholipids, ensuring good biocompatibility and low toxicity. These features enabled highly sensitive tissue detection with a detection threshold in the nanomolar range. The 1525 nm NIR-II emission successfully facilitated imaging in biological tissues, including the stomachs of nude mice and Sprague Dawley rats.

2.2.2 Synthesis of Ln-doped core–shell NPs. Preparation of β-NaYF₄ core nanocrystals (NCs) with different concentrations of Er³⁺ dopants (5, 25, 50, and 100 mol%) was reported by using different starting materials. Subsequently, an inert NaLuF₄ epitaxial shell, approximately 10 nm thick, was grown on these core NCs.⁹²
2.2.2.1 Synthesis of core nanocrystals. Hexagonal-phase (β) NaYF₄ nanocrystals doped with varying concentrations of Er³⁺ ions (5, 25, or 50 mol%) are commonly synthesized using a solvothermal approach involving rare-earth acetate precursors. In a typical method, a mixture of Y(CH₃CO₂)₃·xH₂O and Er(CH₃CO₂)₃·xH₂O, totaling 1.0 mmol, is combined with 6 mL of oleic acid and 17 mL of 1-octadecene in a reaction flask. The mixture is initially heated to 120 °C under vacuum for 1 hour to remove residual water and impurities, then cooled to room temperature. A methanolic solution containing NH₄F and NaOH is subsequently added, and the reaction is stirred for 1 hour to ensure uniform dispersion. Methanol is evaporated by gradually heating the mixture to 70 °C, after which the temperature is increased to 300 °C under an inert argon atmosphere, with the reaction maintained for 60 minutes. This process yields erbium-doped β-NaYF₄ nanocrystals. For shell growth, the core nanocrystals serve as a template, as described in specialized core–shell synthesis protocols. Similarly, hexagonal-phase (β) NaErF₄ nanocrystals are synthesized using a comparable process, with Er(CH₃CO₂)₃·xH₂O as the sole rare-earth precursor, along with adjusted quantities of oleic acid and 1-octadecene. This versatile methodology enables precise control over doping concentrations and crystal phase, facilitating their use in photonic and upconversion applications.
2.2.2.2 Synthesis of sacrificial nanocrystals as shell precursors. Cubic (α) NaLuF₄ nanocrystals are typically synthesized via a modified solvothermal method, utilizing trifluoroacetate precursors. A common approach involves dissolving Lu₂O₃ in aqueous trifluoroacetic acid at elevated temperatures (95 °C) to form a clear solution, followed by evaporation to obtain the trifluoroacetate precursor (Lu(CF₃COO)₃). Subsequent reaction with sodium trifluoroacetate in a solvent mixture of oleic acid, oleylamine, and 1-octadecene under vacuum yields a homogeneous solution. Heating this mixture under argon to high temperatures (∼300 °C) facilitates the nucleation and growth of nanocrystals. Ethanol-induced precipitation, centrifugation, and washing result in well-dispersed nanocrystals in nonpolar solvents. Doping strategies, such as incorporating Nd³⁺ or Yb³⁺, are employed during synthesis by adjusting the molar ratios of Lu₂O₃ with Nd₂O₃ or Yb₂O₃, respectively. These approaches allow for the controlled preparation of doped cubic NaLuF₄ nanocrystals with tailored optical properties, making them suitable for a range of photonic applications (Fig. 9 and Table 2).⁹²

Fig. 9 (a) Schematic illustration of the core–shell nanocrystals structural composition. (b) Representative transmission electron microscopy (TEM) image of the NaErF₄–NaLuF₄ core–shell nanocrystals. (c) Energy level diagram of erbium showing the multiple excitation pathways, and the multiple emission levels leading to upconverted or downshifted emission. (d) Upconversion and downshifted emission photographs of the colloidal dispersion of NaErF₄–NaLuF₄ core–shell nanocrystals at variable excitation wavelengths. Reproduced with permission from ref. 92. © 2017 American Chemical Society. All rights reserved.

Table 2 Summarized core–shell synthesis methods

Nanocrystal type	Synthetic approach	Precursors	Temperature & time	Shell growth method
Footnotes: OA – oleic acid; ODE – 1-octadecene; OLAm – oleylamine; SCNCs – sacrificial core nanocrystals.
β-NaYF4:Er^3+ (core)	Solvothermal	Y(CH3COO)3·xH2O, Er(CH3COO)3·xH2O, NH4F, NaOH, OA, ODE	300 °C, 60 min	N/A (core only)
β-NaErF4 (core)	Solvothermal	Er(CH3COO)3·xH2O, NH4F, NaOH, OA, ODE	300 °C, 60 min	N/A (core only)
α-NaLuF4 (sacrificial precursor)	Modified solvothermal	Lu2O3 + CF3COOH → Lu(CF3COO)3, Na(CF3COO), OA, OLAm, ODE	∼300 °C, multiple steps	Used for shell growth
β-NaYF4@NaLuF4 (core–shell)	Self-focusing ripening	Core NCs + α-NaLuF4 SCNCs in ODE	300 °C, 12 min × 6 cycles	Sacrificial nanocrystal injection
β-NaErF4@NaLuF4:Nd^3+ or Yb^3+	Self-focusing ripening	Core NCs + doped α-NaLuF4 SCNCs	300 °C, 12 min × 6 cycles	Doped shell from sacrificial NCs
Core–shell with variable shell thickness	Incremental shell growth	Aliquots taken after every 2 cycles (∼1 mmol per cycle)	300 °C, per cycle	Thickness controlled by number of cycles

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2.2.2.3 Synthesis of core–shell nanocrystals. Core–shell nanocrystals of hexagonal phase (β) NaYF₄ (X mol% Er³⁺, X = 5, 25, 50, 100) core with NaLuF₄ shell were synthesized using a self-focusing ripening process, as previously reported. In this approach, the core nanocrystals, synthesized as described earlier, were maintained at 300 °C for 1 hour. Sacrificial nanocrystals (0.5 mmol, α-NaLuF4) dispersed in 1 mL of 1-octadecene were injected into the reaction mixture and ripened for 12 minutes. This step was repeated in five additional cycles, each involving the injection of 0.5 mmol of sacrificial nanocrystals followed by ripening for 12 minutes, leading to a total addition of ∼3 mmol of shell precursors. After the final cycle, the mixture was cooled to room temperature, and the core–shell nanocrystals were precipitated by ethanol addition, centrifuged (1900 g, 5 min), washed with ethanol, and dispersed in 10 mL of chloroform.

Similarly, hexagonal phase (β) NaErF₄ core–NaLuF₄ shell nanocrystals doped with Nd³⁺ (X mol%, X = 2, 10) or Yb³⁺ (X mol%, X = 10, 20) were synthesized by replacing the sacrificial α-NaLuF₄ nanocrystals with α-NaLuF4 doped with Nd³⁺ or Yb³⁺, respectively, in corresponding molar concentrations.

To achieve core–shell nanocrystals with variable shell thicknesses, aliquots of the reaction mixture (1 mL) were retrieved at defined stages after every two cycles of sacrificial nanocrystal injection and ripening, corresponding to ∼1 mmol of sacrificial nanocrystals per shell thickness increment. After completing all six cycles (∼3 mmol total), the final solution was cooled, precipitated, centrifuged, and washed as described. The purified aliquots, representing core and core–shell nanocrystals with varying shell thicknesses, were dispersed in 1 mL of chloroform for further analysis. This method provides precise control over shell thickness and composition, enabling the systematic study of their effects on optical properties and other functionalities.⁹²

2.3 Surface engineering of lanthanide-doped nanoparticles for advanced biomedical applications

Surface modification is a cornerstone in tailoring lanthanide-doped nanoparticles (LnNPs) to meet the stringent demands of biomedical applications. Hydrophilicity, biocompatibility, and stability are critical for the effective use of LnNPs in biological environments. Strategies to achieve these properties often involve encapsulating nanoparticles with amphiphilic polymers, such as phospholipids or poly(acrylic acid) (PAA), to form biocompatible micelles. Multilayer coatings with cross-linked polymers further enhance stability and prevent aggregation. For instance, hydrophilic, cross-linked polymer layers on LnNPs, such as Er-doped nanoparticles (ErNPs), have demonstrated remarkable stability in aqueous buffers and serum. These coatings typically consist of multiple layers, including hydrolyzed poly(maleic anhydride-alt-1-octadecene) (PMH), eight-arm branched polyethylene glycol amine (8Arm–PEG–NH₂), and outer layers of mixed methoxy polyethylene glycol amine (mPEG–NH₂) and 8Arm–PEG–NH₂. This design ensures hydrophilicity and water solubility while enabling the conjugation of biological ligands for molecular imaging (Fig. 10).⁶¹

Fig. 10 (a) Schematic illustration of the hydrophilic ErNPs with cross-linking polymeric layers and amine groups on the surface as conjugation sites. (b) DLS spectra of hydrophilic ErNPs with polymeric cross-linked network. (c) NIR-IIb cerebral vascular image (left) by intravenous injection of 200 μL ErNPs (40 mg mL⁻¹) and excitation by a 970 nm LED (30 fps). The luminescence intensity of an inferior cerebral vein was plotted as a function of time (middle), showing the cardiac cycles (upper right) with a heartbeat frequency of 3.67 Hz by fast Fourier transformation (FFT, lower right). Scale bar, 5 mm. (d) The wide-field images show the ErNP luminescence signals in liver and spleen at 1 d and 14 d p.i. Scale bar, 1 cm. (e) The excretion of ErNPs from mouse (n = 3) liver and spleen can be seen by plotting the signal intensity in these organs (normalized to liver signal observed at 1 d p.i.) as a function of time over 2 weeks. (f) Bio-distribution of ErNPs in main organs and feces of ErNP-treated mice (n = 3) at 14 d p.i. All data are presented as means ± s.d. Similar results for n > 3 independent experiments. ID, injection dose. Reproduced with permission from ref. 61. © 2019 Nature. All rights reserved.

Recent advancements have introduced innovative materials such as graphene oxide (GO), which encapsulates oleic acid-capped LnNPs through hydrophobic interactions, providing a versatile platform for further functionalization. These surface engineering techniques enable the nanoparticles to maintain hydrophilicity and stability while allowing bioactive agents, such as antibodies, DNA strands, or fluorophores, to be attached. Such modifications have been shown to significantly enhance the selectivity of near-infrared II (NIR-II) emitting LnNPs for targeted bioimaging and diagnostics, improving signal-to-noise ratios (SNRs) and enabling precise localization to tissues of interest.

The potential of LnNPs extends beyond imaging. Functionalized ErNPs have demonstrated real-time, noninvasive NIR-IIb imaging capabilities, leveraging their bright 1550 nm luminescence for in vivo imaging of cerebrovascular structures through intact scalp and skull. These nanoparticles achieve high temporal and spatial resolution using low-power light-emitting diode (LED) excitation, with superior tissue penetration and reduced phototoxicity compared to traditional laser-based methods. Imaging studies have also revealed dynamic pharmacokinetics, bio-distribution, and efficient excretion of ErNPs, with approximately 90% excreted within two weeks, highlighting their clinical translation potential.

For therapeutic applications, LnNPs are conjugated with photothermal conversion materials such as NiS₂ semiconductors and Cu_2−xS quantum dots, enabling hyperthermia-based cancer therapy. In parallel, fluorophores like Cy7.5 or modifications with azobenzene facilitate multimodal imaging, including dual NIR-II and photoacoustic imaging, expanding diagnostic and theranostic functionalities. Table 3 summarizes the latest advancements in surface engineering, showcasing how these modifications underpin the development of LnNPs for cutting-edge biomedical applications. A comparative study of different biomedical applications of various nanocrystals is tabulated in Table 3.

Table 3 Summary of lanthanide-doped nanoparticles (LnNPs) for biomedical applications and their NIR-II emission mechanisms

Composition/structure	Mechanism of NIR-II emission	Excitation/emission (nm)	Biomedical application	Surface modification
Foot note: NP: nanoparticle; PMH: poly(maleic hydrazide); PEG: poly(ethylene glycol).
Yb^3+–Er^3+ doped NaYF4@NaLuF4	Yb^3+ absorbs 980 nm light and transfers energy to Er^3+ → 1525 nm emission	980/1525	Deep-tissue NIR-II imaging	Inert NaLuF4 shell
Yb^3+–Ho^3+, Yb^3+–Tm^3+, Yb^3+–Pr^3+ systems	Upconversion and Stokes emission depending on Ln pair	980/1155, 1289, 1475	Wavelength-tuned bioimaging	Host lattice tuning
Nd^3+–sensitized Er^3+ system	Nd^3+ → Yb^3+ → Er^3+ energy transfer cascade	800/1525	Fluorescence-guided surgery	Lipid encapsulation
Tm^3+–sensitized Er^3+ system	Tm^3+ sensitizes Er^3+ → intense 1525 nm emission	980/1525	Fluorescence-lifetime imaging	Core/shell tuning
Ce^3+,Zn^2+ co-doped Yb^3+–Er^3+ system	Enhanced relaxation and suppressed upconversion	980/1525	Brightness enhancement for imaging	Zn^2+ doping
Ce^3+/Er^3+ and Ce^3+/Nd^3+ co-doped CaS	Stokes emission under blue LED excitation	Blue LED/1525	Bioassays and responsive sensors	None (solid-state matrix)
β-NaGdF4@Na(Gd,Yb)F4:Er@NaYF4:Yb@NaNdF4:Yb	Multi-step energy transfer through layered shells	800/1525	In vivo NIR-II imaging (e.g., stomach tissue)	Phospholipid coating
Hydrophilic ErNPs with cross-linked polymeric layers	Downconversion luminescence from Er^3+	970/1550	Real-time cerebrovascular imaging	Cross-linked polymers (PMH, PEG)

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3. Characterisation techniques

A comprehensive understanding of the structural, morphological, and optical attributes of NIR-II emitting lanthanide-based nanomaterials requires the integration of multiple advanced characterization techniques. Single-crystal X-ray diffraction (SCXRD) serves as a gold standard for resolving the atomic-level structure of lanthanide complexes and metal–organic frameworks (MOFs), offering detailed insights into coordination geometry, ligand orientation, and crystallographic symmetry. Complementing this, powder X-ray diffraction (PXRD) is widely employed to confirm phase purity, assess crystallinity, and detect possible polymorphs in bulk samples. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) provide high-resolution images to examine surface morphology, particle shape, and size distribution, while high-resolution TEM (HRTEM) can further resolve lattice fringes, aiding in the analysis of crystallographic planes.^73–78

Elemental composition and spatial distribution are verified using energy-dispersive X-ray spectroscopy (EDS) and electron energy loss spectroscopy (EELS), which confirm the successful incorporation and homogeneous distribution of lanthanide ions. Fourier transform infrared spectroscopy (FTIR) is employed to identify key functional groups and confirm metal–ligand coordination, particularly useful in MOF systems. X-ray photoelectron spectroscopy (XPS) further elucidates surface chemical states and oxidation states of metal centers, providing information on chemical environment stability and surface binding interactions.

Optical characteristics, including absorption, excitation, and emission behavior in the NIR-II region, are evaluated through UV-vis-NIR spectroscopy and photoluminescence (PL) spectroscopy, enabling the determination of quantum yields, excitation/emission maxima, and Stokes shifts. Lifetime measurements and temperature-dependent luminescence studies also contribute to understanding non-radiative decay processes and energy transfer efficiency. Together, these techniques provide a holistic and reliable framework for characterizing the structure–property relationships in lanthanide-based nanomaterials, guiding the development of next-generation bioimaging and theranostic platforms.^61,92

4. Optical property designing

Leveraging the unique electronic structures of Ln³⁺ ions, a diverse range of inorganic Ln³⁺-based NIR-II luminescent nanoprobes has been developed (Table 4). These nanoprobes are tailored for various biomedical applications through meticulous engineering of their optical properties. Key strategies include optimizing the host-dopant combinations, fine-tuning dopant concentrations, and controlling the particle morphology. In this section, we explore these approaches in detail, emphasizing how they contribute to enhancing the performance of Ln³⁺-containing NIR-II nanoprobes for targeted bioapplications.

Table 4 Ln³⁺ containing NIR-II luminescent nano probes based on typical Ln³⁺ activators

Activator	Nanoprobe	Ex/Em wavelength (nm)	Ex/Em energy level transition	Ref.
Er^3+	β-NaYF4:50%Gd/20%Yb/2%Er	980/1525	(Yb: ^2F7/2 → ^2F5/2)/(Er: ^4I13/2 → ^4I15/2)	100
	β-NaLuF4:40%Gd/20%Yb/2%Er	980/1525	(Yb: ^2F7/2 → ^2F5/2)/(Er: ^4I13/2 → ^4I15/2)	101
	β-NaLuF4:40%Gd/20%Yb/2%Er (Ce coating)	980/1525	(Yb: ^2F7/2 → ^2F5/2)/(Er: ^4I13/2 → ^4I15/2)	102
	β-NaYF4:18%Yb/2%Er@NaYF4	980/1525	(Yb: ^2F7/2 → ^2F5/2)/(Er: ^4I13/2 → ^4I15/2)	103
	α-NaYbF4:2%Er/2%Ce/10%Zn@NaYF4	980/1550	(Yb: ^2F7/2 → ^2F5/2)/(Er: ^4I13/2 → ^4I15/2)	104
	β-NaGdF4@NaGdF4:Yb/Er(Tm,Ho)@NaYF4:Yb@NaNdF4:Yb	808/1525	(Yb: ^2F7/2 → ^2F5/2)/(Er: ^4I13/2 → ^4I15/2)	105
Nd^3+	NaGdF4:Yb^3+,Nd^3+,Tm^3+	808/1000	(Nd: ^4I9/2 → ^4F5/2)/(Nd: ^4F3/2 → ^4I11/2)	106
	NaNdF4:Mn^2+	808/1058, 1320	(Nd: ^4I9/2 → ^4F5/2)/(Nd: ^4F3/2 → ^4I11/2, ^4F3/2 → ^4I13/2)	107
	CaF2:Y^3+,Nd^3+	808/1058, 1328	(Nd: ^4I9/2 → ^4F5/2)/(Nd: ^4F3/2 → ^4I11/2, ^4F3/2 → ^4I13/2)	108
	NaYF4:Nd^3+@NaYF4	808/1064, 1345	(Nd: ^4I9/2 → ^4F5/2)/(Nd: ^4F3/2 → ^4I11/2, ^4F3/2 → ^4I13/2)	109
	β-NaLuF4:5%Nd	808/1332	(Nd: ^4I9/2 → ^4F5/2)/(Nd: ^4F3/2 → ^4I13/2)	110
	β-NdGdF4:5%Nd@NaGdF4	808/1064	(Nd: ^4I9/2 → ^4F5/2)/(Nd: ^4F3/2 → ^4I11/2)	111
	β-NaYF4:7%Nd@NaYF4	808/1064, 1345	(Nd: ^4I9/2 → ^4F5/2)/(Nd: ^4F3/2 → ^4I11/2, ^4F3/2 → ^4I13/2)	112
	β-NaYF4:30%Yb/0.5%Tm/5%Nd@NaYbF4@NaYF4:30%Nd	808/1000, 1345	(Nd: ^4I9/2 → ^4F5/2)/(Nd: ^4F3/2 → ^4I11/2, ^4F3/2 → ^4I13/2)	113
Ho^3+	Ba2In2O5:Yb^3+,Ho^3+	980/1192	(Yb: ^2F7/2 → ^2F5/2)/(Ho: ^5I6 → ^5I8)	114
Tm^3+	NaYF4:Yb^3+,Tm^3+@NaYF4	980/1475	(Yb: ^2F7/2 → ^2F5/2)/(Tm: ^3H4 → ^3F4)	115
Pr^3+	NaYF4:Yb3+,Pr3+@NaYF4	980/1310	(Yb: ^2F7/2 → ^2F5/2)/(Pr: ^1G4 → ^3H5)	116

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4.1 Excitation strategies for Ln³⁺-containing NIR-II luminescent nanoprobes

The excitation wavelength plays a pivotal role in optimizing the performance of Ln³⁺-containing NIR-II luminescent nanoprobes. The most commonly used excitation wavelength is 980 nm, which aligns well with the absorption band of Yb³⁺ (²F_7/2 → ²F_5/2) (previously discussed in Section 2.2).¹¹⁷ Upon excitation with a commercial 980-nm diode laser, Yb³⁺ efficiently absorbs and transfers energy to activators such as Er³⁺, Tm³⁺, and Nd³⁺. However, the narrow absorption band and low absorption coefficient of Yb³⁺ limit its broader application. Additionally, the 980-nm wavelength poses challenges due to significant water absorption, which can lead to tissue overheating. These limitations have motivated the exploration of alternative excitation strategies to enhance the performance and safety of these nanoprobes.⁹⁴

Beyond NIR excitation sources, X-rays have gained attention for producing NIR-II emission. X-ray excitation offers deep tissue penetration, eliminates autofluorescence, and simplifies optical tomography. For instance, NaYF₄:Yb³⁺,Er³⁺ nanoparticles have been shown to generate distinct NIR-II emission at ∼1530 nm under X-ray irradiation, demonstrating potential for deep-tissue imaging. However, the development of bright, X-ray-excitable Ln³⁺-containing nanoprobes remains an area requiring further exploration.¹¹⁸

To achieve efficient NIR-II luminescence, two primary approaches have been explored: direct excitation and the introduction of sensitizers. Sensitizers, which exhibit broader absorption bands and larger cross-sections than direct excitation sources, transfer energy to activators through an energy transfer (ET) process, enabling efficient NIR-II emission. Among the sensitizers, organic dyes, quantum dots (QDs), and Ln³⁺ ions have been extensively investigated.¹¹⁹

Organic dyes, acting as antennas with large absorption cross-sections, have been widely used to broaden the excitation range of Ln³⁺-containing luminescent nanoparticles. For example, Zou et al. (2012) demonstrated an ET process from the NIR dye IR-806 to NaYF₄:Yb³⁺,Er³⁺ nanoparticles, expanding the excitation range to 720–1000 nm.¹²⁰ Following this work, other dyes, such as indocyanine green (Wang et al., 2018),¹¹⁸ MY-1057 (Zhao et al., 2020),¹²¹ and IR-1061 have been adopted for sensitization, significantly enhancing the absorption cross-section.⁸⁶

Quantum dots (QDs) have also emerged as effective light-harvesting materials. QDs such as CdSe, InP and CsPbX₃ perovskite QDs have shown great potential for sensitizing Ln³⁺ emissions. Among these, CsPbX₃ QDs are particularly noteworthy due to their excellent optical properties and broadband absorption. Pan et al. (2017)¹²² reported NIR emission from Yb³⁺-doped CsPbCl₃ QDs under 365-nm excitation, while Zhu et al.¹²³ (2020) demonstrated CsPbCl₃:Er³⁺,Yb³⁺ QDs with NIR-II emission upon similar excitation (Fig. 11).¹⁰¹

Fig. 11 Excitation manipulation of Ln³⁺-containing NIR-II luminescent nanoprobes. (A) Schematic illustration of the ET from Ce³⁺ to Er³⁺ and Nd³⁺ in CaS NPs. (B) Simplified energy levels of Ce³⁺, Er³⁺, and Nd³⁺ in CaS NPs, showing the proposed ET processes for the population of ⁴I_13/2 of Er³⁺ and ⁴F_3/2 of Nd³⁺ through sensitization by Ce³⁺. The dashed, dotted and full arrows represent the ET, nonradiative relaxation and radiative transition processes, respectively. (C) Schematic design of the as-synthesized NaYF₄:Tm³⁺@NaYF₄ and NaYF₄:Tm³⁺,Er³⁺@NaYF₄ NPs excited by a 1208-nm laser (D) Simplified ET pathway from Tm³⁺ to Er³⁺. (E) X-IR system used to image Ln³⁺-doped NPs consists of a highly sensitive NIR-II detector and X-ray irradiator. (F) Distinct focal luminescence was visualized away from the injection site near the animal's axillary and brachial lymph nodes. Reproduced with permission from ref. 116. © 2024 Cell Press. All rights reserved.

Ln³⁺ ions themselves serve as sensitizers in some systems. For instance, Nd³⁺, which exhibits multiple absorption bands and a relatively large cross-section, enables excitation at 808 nm, where water absorption is significantly lower (0.02 cm⁻¹) compared to 980 nm (0.48 cm⁻¹). This shift minimizes laser-induced tissue heating. Nd³⁺-sensitized nanoparticles, such as NaGdF₄:Yb³⁺,Nd³⁺,Tm³⁺ (Tan et al., 2018)¹⁰⁶ and NaGdF₄:Nd³⁺@NaGdF₄:Tm³⁺,Yb³⁺ (Wang et al., 2014),²¹ have been proposed for NIR-II applications. Similarly, Er³⁺ has been used in NaErF₄:Yb³⁺@NaLuF₄ nanoparticles, enabling efficient excitation at ∼800 nm (Wang et al., 2018).¹¹⁸ Er³⁺ also facilitates deep-tissue imaging through its absorption peak at ∼1530 nm, as demonstrated in NaErF₄:Ln³⁺@NaYF₄ nanoparticles, where Ln³⁺ = Ho³⁺ or Nd³⁺ (Liu et al., 2018).⁹⁵

Tm³⁺ has emerged as another promising sensitizer, capable of absorbing NIR photons at 1208 nm and 808 nm and transferring energy to activators. For example, NaYF₄:Tm³⁺,Er³⁺@NaYF₄ nanoparticles produce 1525 nm luminescence through the ET process under 1208-nm excitation (Zhang et al., 2019).⁴⁶ Similarly, NaYF₄:Tm³⁺,Ho³⁺@NaYF₄ nanoparticles exhibit 1180 nm emission from Ho³⁺ under 808-nm excitation.⁷⁴

4.2 Emission manipulation in Ln³⁺-containing NIR-II luminescent nanoprobes

Lanthanide ions (Ln³⁺) offer a rich array of energy levels, enabling the generation of abundant wavelengths in the NIR-II region. These ions are characterized by much narrower emission bandwidths compared to quantum dots (QDs) and organic dyes, minimizing signal interference in both in vivo bioimaging and in vitro bio-detection. Consequently, significant efforts have been devoted to fine-tuning NIR-II emissions to meet the specific requirements of various biomedical applications (Fig. 12).⁹⁹

Fig. 12 Emission manipulation of Ln³⁺-containing NIR-II luminescent nanoprobes (A) rare-earth nanoprobes consist of a NaYF₄:Yb³⁺,Ln³⁺ core (Ln³⁺: Er³⁺, Ho³⁺, Tm³⁺ or Pr³⁺) surrounded by an undoped shell of NaYF₄. (B) NIR-II emissions from different Ln³⁺ emitters like Ho³⁺, Pr³⁺, Tm³⁺, and Er³⁺. (C) 1185, 1310, 1475, and 1525 nm emissions of Ho-, Pr-, Tm-, and Er-doped NPs are attributed to the ⁵I₆/⁵I₈, ¹G₄/³H₅, ³H₄/³F₄, and ⁴I_13/2/⁴I_15/2 transitions, respectively. (D) Schematic illustration of the ET in the NaErF₄:Ho³⁺@NaYF4 NPs. (E) Simplified energy levels of Er³⁺,Ho³⁺ in NaErF₄:Ho³⁺@NaYF4 NPs, showing the proposed ET process through sensitization of Er³⁺. (F) Emission spectra of the obtained NIR-II NPs. Reproduced with permission from ref. 116. © 2024 Cell Press. All rights reserved.

For instance, Nd³⁺-doped NaGdF₄ nanoparticles (NPs) exhibit three photoluminescence (PL) bands at 900, 1050, and 1330 nm upon 740-nm excitation. These bands correspond to the transitions from ⁴F_3/2 to ⁴I_J (J = 9/2, 11/2, 13/2) and fall within the “optical transparency window,” making NaGdF₄:Nd³⁺ NPs ideal for high-contrast in vivo imaging (Chen et al., 2012).¹²⁴ Beyond Nd³⁺, other Ln³⁺ ions such as Pr³⁺ (¹G₄ → ³H₅), Ho³⁺ (⁵I₆ → ⁵I₈), Er³⁺ (⁴I_13/2 → ⁴I_15/2), and Tm³⁺ (³H₄ → ³F₄) also demonstrate strong potential for NIR-II luminescence. Their emissions, spanning the 1000–1700 nm range, enable the design of multicolor probes for multispectral imaging and multiplexed detection (Fig. 12A–C) (Naczynski et al., 2013).¹²⁵ Ratiometric optical nanoprobes have emerged as a powerful approach for enhancing signal-to-background ratios and improving the reliability of bioimaging and biosensing. By leveraging non-overlapping emissions, several Ln³⁺-containing NIR-II luminescent materials with dual or multiple emissions have been developed. For example, NaErF₄:Ho³⁺@NaYF₄ NPs exhibit efficient emission at 1180 nm upon 1530-nm excitation (Fig. 12D–F) (Liu et al., 2018). Here, Er³⁺ serves as both the sensitizer and emitter, with emissions peaking at 650 nm (⁴F_9/2 → ⁴I_15/2) and 980 nm (⁴I_11/2 → ⁴I_15/2), respectively. Additionally, energy transfer (ET) from Er³⁺ to Ho³⁺ generates an emission peak at 1180 nm. These distinct emissions have enabled the design of novel ratiometric luminescent nanoprobes (e.g., I₉₈₀/I₁₁₈₀) for dynamic in vivo inflammation detection.⁶

4.3 Photoluminescence lifetime manipulation

PL lifetime plays a vital role in time-domain bioimaging, helping to minimize inhomogeneous signal attenuation in biological tissues. Structural modifications such as surface passivation and core–shell designs have proven effective in enhancing PL lifetimes. For example, the nonradiative relaxation caused by surface defects was mitigated by coating inert shells on Ln³⁺-doped NPs. In α-NaYbF₄@CaF₂ NPs, the PL lifetime was tuned from 33 ms to 2.18 ms by varying the shell thickness. An optimal shell thickness of 2.6 nm prevented surface-quenching-induced concentration quenching, achieving a PL lifetime close to the radiative lifetime of Yb³⁺.¹¹³

Advanced core/multi-shell architectures have further expanded the ability to manipulate PL lifetimes. Fan et al. (2018) introduced a systematic approach using a four-layer structure, including an inert core, an activation layer (NaGdF₄:Yb³⁺,Er³⁺), an energy relay layer (NaYF₄:Yb³⁺), and an outer absorption layer (NaNdF₄:Yb³⁺).⁹³ This design allowed PL lifetime tuning in two directions: increasing the relay layer thickness prolonged the lifetime, while increasing the Er³⁺ concentration accelerated energy conversion, shortening the lifetime. The resulting PL lifetimes spanned three orders of magnitude, enabling over 10 distinct lifetime identities for time-resolved imaging. Similar strategies have been employed for other Ln³⁺ ions, including Ho³⁺ (1155 nm), Pr³⁺ (1289 nm), Tm³⁺ (1475 nm), and Nd³⁺ (1060 nm).¹¹⁵

Incorporating NIR-II dyes with Ln³⁺-doped NPs provides another effective pathway for tuning PL lifetimes. Zhao et al. (2020) developed a Förster resonance energy transfer (FRET) nanoprobe using β-NaYF₄@NaYF₄:Nd³⁺ NPs as donors and the NIR-II dye MY-1057 as an acceptor. This Ln³⁺-cyanine FRET system reduced the PL lifetime of Nd³⁺ from 305 ms to 75 ms, with lifetime recovery enabled by MY-1057 degradation in response to reactive nitrogen species.

4.4 Photoluminescence intensity improvement

Despite the potential of Ln³⁺-containing nanoprobes, their low PL intensity, resulting from the small absorption cross-section of Ln³⁺ ions, remains a significant bottleneck. Researchers have tackled this issue by optimizing dopant spatial distribution, improving surface passivation, enhancing energy transfer pathways, and refining host matrices. High doping concentrations can theoretically enhance PL intensity by providing more emitters, but excessive dopant concentrations often lead to concentration quenching. Spatial isolation strategies have been employed to mitigate this issue. For example, in NaGdF₄:Nd³⁺@NaGdF₄:Tm³⁺,Yb³⁺ NPs, the spatial separation of Nd³⁺ and Tm³⁺ ions reduced quenching, improving NIR-II emission intensity by a factor of 7 compared to core-only counterparts (Johnson et al., 2017).⁹²

In addition to dopant distribution, surface defects are another major source of energy loss. The epitaxial growth of inert shells has been widely used to address this. For instance, NaYF₄:Er³⁺ NPs coated with an inert NaLuF₄ shell exhibited a 659-fold enhancement in NIR-II luminescence at 1525 nm (⁴I_13/2 → ⁴I_15/2) compared to uncoated counterparts (Johnson et al., 2017).⁹² By integrating strategies for PL lifetime manipulation and intensity enhancement, Ln³⁺-containing NIR-II nanoprobes are increasingly optimized for advanced bioimaging and sensing applications. These developments not only improve the functionality of the nanoprobes but also ensure their reliability and efficiency in diverse biomedical contexts.

5. Biomedical applications of NIR-emitting biomaterials

5.1 Medical imaging

5.1.1 Techniques and advancements in fluorescence imaging. Medical imaging technologies received a major breakthrough through fluorescence imaging because it provides real-time, high-resolution observation of biological structures, together with process visualization. Modern advancements in biomaterials producing near-infrared (NIR) light emissions improve fluorescence imaging with longer tissue examination capabilities, minimized phototoxicity, and better signal detection ratios. Biomaterials that emit near-infrared light overcome the limitations of photobleaching and autofluorescence with their stable and adjustable fluorescence properties through quantum dots, rare-earth-doped nanoparticles, and organic small molecules. Novel imaging techniques, including two-photon excitation and super-resolution microscopy, advance NIR fluorescence imaging capabilities by enabling precise molecular tracking with subcellular resolution capabilities.¹²⁶

NIR and ultrasound triggered Pt/Pd-engineered cluster bombs were designed to treat solid liver tumors, which deeply insert into hepatic cancer cells membranes to target sonodynamic and photothermal therapy. They generate physical forces by fast expansion and exploration of nanodroplets into liver cells through ultrasound (US) and NIR. With the applications of these technologies Pt/Pd nanotechnology-based alloys modify O₂ and H₂O₂ to increase instant SDT efficiency and hypoxia, which are highly efficient to give photothermal outcomes of NIR.^107,127

Forster resonance energy transfer (FRET) systems enable functional biochemical interaction assessments, which help clinicians to identify diseases early and manage specific medicine distribution pathways. Recent bio-conjugation tactics have boosted the specificity of NIR-emitting probes to effectively detect biomarkers that indicate cancer conditions, neurodegenerative diseases, and infections. Scientists have created new optimization strategies that improve NIR fluorophores for their use in bioimaging, together with sensing applications. Scientists modify carbon nanomaterial structures by adding electron-acceptor or donor elements to manage energy levels, which ultimately optimizes their fluorescence, together with wavelength extension properties. Molecular frameworks need to be designed rigidly, and nanocarriers must contain encapsulated materials to suppress nonradiative decay, which improves photostability and brightness. Anti-quenching performance of quantum yield gets better, and quenching effects drop significantly because of developments in aggregation-induced emission, together with donor–acceptor systems. Fluorophores became better for precise sensing through the implementation of environment-specific properties, including pH or polarity sensitivity. Hybrid technology approaches that combine biomolecules and nanoparticles creation allow scientists to develop targeted imaging and therapeutic solutions. The development of NIR fluorophores for high-resolution real-time imaging and accurate disease diagnoses gains weight since scientists continuously integrate new techniques for their advancement. The advancement of biomedical applications, along with fluorescence sensing technology steadily forward through the innovative practices of molecular engineering.¹²⁸ Through the combination of NIR fluorescence imaging with machine learning algorithms, the medical community achieves better diagnostic outcomes as well as quantitative assessment capabilities. These combinatorial methods were used to combine the cancer-associated macrophages and pro-inflammatory phenotypes for their role as immunomodulation enhancers. For this reason, mesoporous silica nanoparticles (F108-hMSNs) were encapsulated with the immunomodulator resiquimod to kill cancerous cells via prolonged macrophage stimulation (Fig. 13).

Fig. 13 (a) Schematic representation of particle synthesis and preparation (not to scale). (b) Size distribution of MSNs, F108-hMSNs, and R848@F108-hMSNs. Inset: TEM image of MSNs. (c) Zeta potential measurements of MSNs, F108-hMSNs, and R848@F108-hMSNs. **p < 0.01, *p < 0.001 (ANOVA with Tukey's multiple comparison test, N = 3, mean ± SE). Reproduced with permission from ref. 129. © 2024 American Chemical Society. All rights reserved.

This work gives strong evidence that mechanical activation enhanced by self-engineered nanoparticles gives a prospective treatment option against the immunologically targeted long-acting carcinogenic cells.¹²⁹ The use of biocompatible NIR fluorophores in vivo imaging helps physicians develop both minimally invasive procedures while building personalized medicine programs. The gradual advancement of research demonstrates that the partnership between NIR-emitting biomaterials and multimodal imaging methods, including photoacoustic imaging and magnetic resonance imaging (MRI), creates opportunities for advanced disease tracking and theranostics capabilities.

5.1.2 Case studies and clinical applications. The clinical world has shown strong potential for NIR-emitting biomaterials through their application in disease diagnosis and surgical navigation and targeted therapy. Several field experiments demonstrate their practical application in biomedical diagnostic procedures. NIR-fluorescent probes serve as important tools for cancer surgical procedures as they enhance both diagnostic precision and protect normal tissue during procedures for mapping sentinel lymph node locations. One important near-infrared (NIR) photosensitive molecule utilized in imaging and photothermal (PTT) and photodynamic (PDT) treatment is indocyanine green (ICG). ICG converts absorbed light into heat for tumour ablation and produces reactive oxygen species (ROS) to kill bacteria and cancer cells when exposed to NIR light. However, its efficacy is limited by issues like poor water quality and optical stability. ICG-based composite nanomaterials have been created to improve stability and multifunctionality in order to overcome these problems. So, the NIR with composite material design and molecular structure and properties of ICG was employed to add to their clinical applications.¹³⁰

A lysosome-targeted and pH-responsive nanophototheranostic for near-infrared II (NIR-II) fluorescence imaging-guided photodynamic therapy (PDT) and photothermal therapy (PTT) was developed and currently employed for the treatment of nasopharyngeal carcinoma (NPC). In this study, the lysosome-targeted S–D–A–D–S-type NIR-II phototheranostic molecule (IRFEM) is encapsulated within the acid-sensitive amphiphilic DSPE-Hyd-PEG2k to form IRFEM@DHP nanoparticles (NPs) (Fig. 14). The formulated, IRFEM@DHP exhibits a good result in buildup in the acidic lysosomes for enabling the issue of IRFEM, which could disrupt lysosomal function by producing a quantity of heat and ROS under laser irradiation.¹³¹

Fig. 14 Schematic illustration of IRFEM@DHP for lysosome-targeted NIR-II fluorescence imaging-guided phototherapy of nasopharyngeal carcinoma (NPC). (a) IRFEM@DHP nanoparticles are formed via self-assembly of lysosome-targeting IRFEM and acid-sensitive DSPE-Hyd-PEG₂k, disassembling under acidic conditions to release IRFEM. (b) Following systemic administration, IRFEM@DHP accumulates in tumor tissue via the enhanced permeability and retention (EPR) effect, enters lysosomes, and disassembles. Upon light irradiation, IRFEM generates heat and reactive oxygen species (ROS), causing lysosomal rupture and inducing cell death. Reproduced with permission from ref. 131. © 2024 American Chemical Society. All rights reserved.

In another study, pluronic F-127 (PF127) and sodium alginate (SA)-based hydrogel have targeted specific tissue via injection. The PF127/SA hydrogel was united with polymeric short-filaments (SFs) comprising an anti-inflammatory agent ketoprofen, and stimuli-responsive polydopamine (PDA) particles. This formulation with hydrogel injectability and variable strength has led to excellent result significant results in S. aureus and E. coli of NIR light irradiation.¹³²

Clinician uses the FDA-approved NIR dye indocyanine green (ICG) in clinics as a breast cancer surgical tool for tumor margin visualization, leading to more accurate surgical resections. NIR-emitting nanoparticles enable non-invasive imaging of deep tumors, which helps medical experts make early disease diagnoses for pancreatic cancer, glioblastoma, and other related diseases. NIR-fluorescent biomarkers serve dual roles in medical imaging by assisting cardiovascular examinations, which detect arterial plaque formations and provide continuous observation of blood circulation pathways. NIR-based imaging agents track amyloid-beta plaques in Alzheimer's disease models during research studies to monitor the disease's evolutionary processes. The use of NIR fluorescence imaging improves wound healing assessments through live observation of tissue oxygenation alongside observation of new vessel formation during angiogenesis. Bifunctional scaffolds for photothermal therapy and bone regeneration, photothermal therapy combined with multiple therapies (immunotherapies, chemotherapies, and chemo dynamic therapies, magnetic, and photodynamic therapies), target strategies have been employed in Bone tumors, particularly osteosarcoma among children and adolescents.¹³³ Current medical practice advances demonstrate that NIR-emitting biomaterials integrated with advanced imaging modalities will transform personalized medicine through earlier disease detection, precise surgical techniques, and targeted therapeutic practices.

5.2 Phototherapy

5.2.1 Mechanisms and efficacy of photodynamic and photothermal therapies. The biomedical field uses NIR-emitting biomaterials to perform photodynamic therapy (PDT) along with photothermal therapy (PTT) as minimally invasive therapeutic procedures for cancer treatment, as well as treatment of other diseases. The use of NIR-activated photosensitizers through PDT allows reactive oxygen species (ROS) formation that activates targeted deadly actions in diseased tissue regions. The treatment reaches tumours effectively because it offers spatial-temporal accuracy, which decreases damage to adjacent healthy tissue. It was found that the nitrogen reactive species are more harmful than the reactive oxygen species. Keeping this point in mind, two 5th-order nonlinear optical materials, FB–Fe(III)/SNP@PEG and FB–Fe(II)–FB/SNP@PEG, were synthesized and evaluated with the addition of near-infrared-II and have significantly shown synergic results, ROS and RNS, FBFe(III)/SNP@PEG induced mitochondrial damage and DNA fragmentation, and inhibited carcinomas (Fig. 15).

Fig. 15 (a) Schematic illustration of the preparation of FB–Fe(III)/SNP@PEG. (b) Schematic illustration of the preparation of FB–Fe(II)–FB/SNP@PEG. (c) Crystal structure of FB–Fe(III). (d) Crystal structure of FB–Fe(II)–FB. All hydrogen and solvent molecules are omitted for clarity. (e) Three-photon absorption spectrum of FB–Fe(III) (λ_ex, 1900 nm; c = 1 mM) and FB–Fe(III)/SNP@PEG (λ_ex, 1600 nm; c = 1 mM) through the Z-scan method. (f) Three-photon absorption cross section of FB–Fe(II)–FB (λ_ex, 1900 nm; c = 1 mM) and FB–Fe(II)–FB/SNP@PEG (λ_ex, 1600 nm; c = 1 mM). (g) Three-photon absorption cross section of FB–Fe(III) and FB–Fe(III)/SNP@PEG (λ_ex, 1200–1900 nm; c = 1 mM). (h) Threephoton absorption cross section of FB–Fe(II)–FB and FB–Fe(II)–FB/SNP@PEG (λ_ex, 1200–1900 nm; c = 1 mM). Reproduced with permission from ref. 134. © 2024 American Chemical Society. All rights reserved.

Scientists have developed photosensitizers, including porphyrins and phthalocyanines, and nanocarbon-based materials to boost their capacity for NIR light absorption, thus improving both treatment depth and effectiveness. The alternative method, PTT, works through heating cancer cells by using NIR-responsive nanomaterials, including gold nanorods, carbon nanotubes, and graphene derivatives that transform absorbed NIR light energy into thermal energy. The therapy called PTT provides deeper penetrating powers to tissue and shows minimal harm to patients, thus serving as a robust substitute therapy to traditional approaches. Success in tumour ablation occurs when PDT combines with PTT through synergistic phototherapy since this method simultaneously generates both oxidative stress and hyperthermia for improved treatment effectiveness. Strategic integration of these therapies with drug delivery systems linked to fluorescence imaging methods generates enhanced therapeutic precision and treatment evaluation capabilities. NIR-emitting biomaterials show promising prospects for personalized medicine through safer and improved treatments that include cancer therapy, antimicrobial care, and tissue regeneration and recovery.

In another study, PDA@Ag/SerMA microneedles were organized by uniting the photothermal possessions of polydopamine (PDA), the antimicrobial properties of argentum (Ag), and the capability of sericin methacryloyl (SerMA) to encourage cell mitosis to hasten wound curing and treat diabetic ulcer lesions Escherichia coli and Staphylococcus aureus, 808 nm NIR irradiation for a potential solution to wound healing of diabetic foot ulcer (DFU).¹³⁵

NIR emitting biomaterials are very useful in biomedical imaging because they can penetrate deep tissue, have low light scattering, and have low autofluorescence in biological tissues. The most appealing ones are lanthanide-doped nanoparticles (LnNPs) due to narrow emission peaks, long luminescence lifetimes, high photostability, and low toxicity. These characteristics render them suitable when considered as candidates for non-invasive high-resolution medical imaging. Using cancer diagnosis as an example, fluorescence imaging with lanthanide-doped nanoparticles is one of its widespread uses.¹³⁶ For example, upconversion nanoparticles made in the NIR when excited by light of 980 nm have already been functionalized with tumor-targeting ligands such as folic acid, allowing specific imaging of tumor cells. Their brilliant upconversion emission allows real-time monitoring of tumor progression with a low background. Magnetic resonance imaging (MRI) Gd³⁺-doped nanoparticles offer strong contrast enhancement capabilities.⁵⁴ With these multimodal nanoparticles, it is possible to provide simultaneous NRI fluorescence to visualize optical imaging and MRI contrast, which can also be performed in a dual-modality diagnosis to improve the accuracy. Likewise, deeper tissue imaging with improved signal-to-noise ratios is being incorporated into the NIR-II window (1000–1700 nm) by employing Nd³⁺-doped nanoparticles. Moreover, Nd³⁺ or Yb³⁺-doped nanoparticle-based photoacoustic imaging can enjoy the light absorption of NIR and provide the image of deep-lying tissue/tumor via ultrasonic imaging. These imaging plans are being applied to plan the surgical removal of cancerous tumors or evaluate vascular defects in real-time.¹³⁷

In a similar way, organic photothermal agents (PTA) with an outstanding ultra-high photothermal conversion efficiency (PCE) were developed from rationally designed perylene diimide (PDI) with an electron-donating cyclohexylamine moiety, significantly enhancing its NIR captivation, resulting in super photothermal translation. These molecules are subsequently compressed within silica nanocapsules, which have biocompatibility, colloidal stability, and exhibit extended blood matrix movement and empower targeted gathering at the cancer location.¹³⁸

5.3 Recent clinical trials and outcomes

The results from recent clinical trials confirm the effectiveness of PDT and PTT as state-of-the-art biomedical applications of NIR-emitting biomaterials for treating cancer and various other diseases. PDT remains extensively investigated for medical treatment of skin, lung, and esophageal cancers by using both photofrin and talaporfin sodium as approved photosensitizers by the FDA. A PDT clinical trial for treating head and neck cancer achieved major tumour reduction rates while maintaining low side effects for increased patient survival statistics. Studies of the new generation NIR photosensitizers in glioblastoma treatment aim to enhance treatment depth and performance rates. The clinical evaluation of PTT has been possible through developments using gold nanoparticles together with carbon-based nanomaterials. Clinical tests involving silica-coated gold nanorods (AuroLase®) for prostate cancer treatment showed both specific accumulation in tumours and effective heating procedures without major harmful effects. Breast cancer patients involved in research demonstrated that PTT generated better tumour reactions when integrated with immune checkpoint inhibitors while boosting immune system activities. Scientists are exploring treatment approaches that unite PDT with PTT strategies.

As blood brain barrier plays a vital role in the delivery of efficient drugs through the development of restrictions in synaptic plasticity and dopamine upregulation. Some suitable and fast-acting delivery systems have been developed to release these synaptic neurotransmitters. This visual and magnetic response system (MRS), CFs@DP, contains frameworks (CFs), domperidone (DP), and carbonized MIL-100 (Fe), that was targeted to the brain through the nasal route (Fig. 16). With the double stimulation of catecholamine-induced complexation and NIR irradiation, CFs@DP release iron ions and DP that affect the upregulate of brain-derived neurotrophic factor (BDNF) dopamine receptors, to accomplish a beneficial result.¹³⁹

Fig. 16 The synthesis of CFs@DP and its application in magnetic target-based drug delivery and neurotherapy. (a) Synthesis of CFs@DP. (b) Magnetic targeted nasal administration delivery system of CFs@DP inspired by a snuff bottle. (c) The mechanism of toxicity reduction and controllable release. The mechanism of therapeutic effect in (d) “during treatment phase” and (e) “after drug withdrawal phase”. Reproduced with permission from ref. 139. © 2024 The Author(s). Advanced Materials published by Wiley-VCH GmbH under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).

Organic agents comprising photoacoustic duplex imaging and NIR-II fixed with photothermal conversion plan significant glioblastoma phototheranostics, which further amplified to display cancer targeting and BBB penetrability. In that study, the aza-BODIPY scaffold, constructed to exhibit remarkable NIR-II/photoacoustic imaging routine performance for cancer targeting and BBB penetrability through receptor-based transcytosis, allowing for accurate and effective phototherapy, presents innovative standpoints on the expansion of progressive complexity imaging probes and brain cancer therapeutics.¹⁴⁰ Research observations on metastatic melanoma analysing how dual treatment strategies generated heat stress and oxidative effects, which produced intensive immune system activation. Targeted near-infrared (NIR) fluorescent silica nanoparticles (FSNs), size of 50–200 nm, conjugated their surface with an antibody to carcinoembryonic antigen (CEA), were targeted HT29 (CEA positive) and HCT116 (CEA negative) cells for molecular imaging biomarker for early diagnosis of colorectal cancer (CRC).¹⁴¹

A novel method, high epidermal growth factor receptor (EGFR)-targeting oxygen-saturated nanophotosensitizers designed as CHPFN-O₂, helps to introduce immunological responses by adding Fc receptor (FcR) through expressing immune effector cells for tumor cells with good safety expressions in malignancies.¹⁴² Cells maintain the most abundant nonprotein biothiol substance as glutathione (GSH), which contains glutamate and glycine alongside cysteine in a three-peptide sequence for cellular redox balance defense purposes. GSH functions as a fundamental antioxidant that defends biological molecules by eliminating ROS alongside its antioxidant regeneration capabilities. Cells measure their redox status through dynamic changes in reduced glutathione (GSH) versus its oxidized form (GSSG), which determine several physiological as well as pathological events. A glutathione peptide conjugated (NIR–SiNPs–GSH), fluorescent ratiometric near-infrared silicon nanoparticle (NIR–SiNP), favorable biocompatibility probe was employed as a synthetic chemical tool with significant results for early tumor detection.¹⁴³

In another investigation it was seen that zeolitic imidazolate framework 8-coated Prussian blue nanocomposite (ZIF-8@PB), encapsulated with quercetin (QCT) has exhibited significantly increased the adenosine triphosphate levels, reduced the oxidative stress levels, and reversed dopaminergic neuronal damage as well as PD-related behavioral deficits via near-infrared radiation (NIR) response and penetrated through the BBB to the site of mitochondrial. So, this study concludes that NIR radiation, the biocompatible ZIF-8@PB–QCT nanocomposite, could be employed in therapeutics for neurodegenerative diseases.¹⁴⁴ A novel approach utilizing thermoresponsive mesoporous silica nanoparticles (MSN) as a delivery system for the chemotherapeutic drug doxorubicin was employed by photothermal agent copper sulfide (CuS) nanoparticles potent photothermal properties. In vivo experiments (4T1 tumor-bearing mouse model), including the breast carcinoma cells (4T1), have shown the synergistic effects towards anti-cancer activity in the combination of chemotherapy and photothermal therapy (PTT).¹⁴⁵

Various NIR light-responsive groups, such as ortho-nitrobenzyl (ONB), coumarin (CM), spiropyran (SP), and 2-diazo-1,2-naphthoquinone (DNQ) derivatives, in the expansion of long-wavelength light-responsive nanocarriers have been developed for their applications as polymeric resources, such as hydrogels, micelles, for diagnosis and smart drug delivery systems. NIR light application activates these molecules, which leads to controlled drug delivery release. The research establishes standard experimental designs for NIR-triggered drug delivery assessments to demonstrate different light irradiation approaches. The extensive evaluation aids in understanding NIR-triggered drug delivery systems, together with their practical usages in targeted therapeutic approaches.¹⁴⁶

Research trials indicate that NIR-emitting biomaterials present strong clinical promise for cancer treatment while delivering precise therapeutic methods for safer oncological patient care.

5.4 Biosensing

5.4.1 Development of NIR-based biosensors. The creation of NIR-based biosensors, which provide highly sensitive real-time identification of biomolecules, as well as disease markers and physiological parameters. Advanced biosensors with superior optical properties have been developed through the implementation of quantum dots, upconversion nanoparticles, and organic fluorophores that emit near-infrared light. These materials help achieve deep tissue penetration and minimal background autofluorescence, together with high photostability. The biosensors employ FRET along with SPR or enzymatic reactions to detect particular biomolecular targets with excellent sensitivity and selection capabilities. The evolution of NIR-based biosensor technology includes the manufacturing of integrated sensors for continuous health monitoring, which can be worn or inserted into the body. Scientists have developed NIR-sensitive glucose biosensors to provide non-invasive blood sugar assessment for treating diabetic patients effectively. The combination of NIR biosensors with microfluidic platforms permits real-time cancer biomarker identification, which leads to higher accuracy in early medical diagnoses and tailored therapeutic plans.

Luminescent materials known as PLNs absorb outside illumination energy before they slowly release it as a glow when in darkness to produce extended visibility. Determining effective ways to develop NIR-PLNs remains essential to boost long-afterglow emissions for biomedical applications that need advanced autofluorescence suppression. Receivers using NIR-PLNs demonstrate excellent progress in biosensing and bioimaging when focusing their operations within the first near-infrared window (NIR-I, 700–900 nm). Yet their implementation remains restricted by the barrier of tissue autofluorescence and light scattering limitations. Second near-infrared window (NIR-II, 1000–1700 nm) fluorescence imaging performs better due to its ability to penetrate deeper into tissue while delivering enhanced resolution, together with a better signal-to-noise ratio. Specific applications derived from the above combinations would optimally enhance near-infrared photoluminescence technology for medical diagnostics applications in carcinomas.¹⁴⁷ Various NIR light-responsive groups, such as ortho-nitrobenzyl (ONB), coumarin (CM), spiropyran (SP), and 2-diazo-1,2-naphthoquinone (DNQ) derivatives, in the expansion of long-wavelength light-responsive nanocarriers have been developed for their applications as polymeric resources, such as hydrogels, micelles for diagnosis, and smart drug delivery systems (Fig. 17). NIR light application activates these molecules, which leads to controlled drug delivery release. The research establishes standard experimental designs for NIR-triggered drug delivery assessments to demonstrate different light irradiation approaches. The extensive evaluation aids in understanding NIR-triggered drug delivery systems, together with their practical usages in targeted therapeutic approaches.¹⁴⁸

Fig. 17 Schematic representation of a near-infrared light-responsive polymeric material for a smart drug delivery system. Reproduced with permission from ref. 148. © 2022 Elsevier. All rights reserved.

The application of NIR biosensors for identifying neurological disease indicators, including Alzheimer's disease amyloid-beta plaques, has led researchers to establish new paths for early diagnosis. When we talk about the challenges for the treatment of cancerous cells, triple-negative breast cancer (TNBC) and TNBC with metastasis are a challenging step in the current scenario. To overcome this challenge, photodynamic therapy (PDT) has a prominent anticancer effect, and combining PDT with chemotherapy may provide significant results against breast cancer therapy. So, doxorubicin (Dox) and IR780 liposomes were formulated and evaluated against breast cancer cells (4T1 cells) and macrophage cell membranes. It was found that, in mouse models, PEGylated liposomes loaded with Dox and IR780 can dramatically enhance breast cancer treatment following laser irradiation by camouflaging the hybrid cell membranes of breast cancer and macrophages.¹⁴⁹

5.5 Applications in disease diagnosis and physiological monitoring

NIR-based biosensors function today as essential diagnostic evaluation and monitoring devices that deliver precise real-time detection of biomarkers alongside physiological compounds through nondestructive approaches. Researchers use biosensors that utilize NIR-emitting biomaterial properties, which include strong tissue penetration with minimal background fluorescence and stable performance under light conditions for in vivo applications. The diagnosis of medical conditions uses NIR biosensors to find cancer biomarkers by detecting circulating tumour cells and specific proteins which occur in breast cancer, as well as lung cancer and prostate cancer. Quantum dot-based NIR biosensors perform early cancer screenings through the detection of minimal tumour marker concentrations found in blood and tissue samples. The real-time detection of amyloid-beta plaques in Alzheimer's disease becomes possible through NIR fluorescence imaging which also provides tools for diagnosing and tracking disease progression. Expert researchers have engineered NIR biosensors that quickly identify bacteria and viruses, as well as other infectious disease pathogens. The implementation of NIR-based wearable sensors includes devices for monitoring diabetes-related glucose levels and tracking blood oxygen saturation during critical care, as well as measuring metabolic pH changes in various disorders. Implantable NIR biosensors provide ongoing cardiovascular health observation possibilities through their ability to detect biomarkers connected to heart symptoms and blood clot development. NIR biosensors linked with artificial intelligence systems and wireless capabilities have expanded their medical capacity into real-time personalized healthcare delivery.

Materials’ polymerization, crosslinking, as well as photothermal or photodynamic, with the utilization of NIR, grasps a high translational potency due to the slight interactions with the organic components and higher diffusion capacity in humanoid skin tissues, which has been explored for active NIR-responsive wound healing process at the tissue site.¹⁵⁰ Theranostic claims of polymer-based micro/nanorobots (MNRs) with bioimaging, biosensing, drug delivery, and tissue engineering discourse the trials that must be overcome to simplify the translational expansion of polymeric MNRs with upcoming perceptions for further medical development for various health applications.¹⁵¹

External stimuli regulate cellular functions through combinations of electricity, light, ultrasound, and magnetism, which biomaterials help to execute these processes. The cellular functions of electric and biochemical signalling, along with drug transport, cell loading, and mechanical stress regulation, occur when stimuli interact with biomaterials. Biomedical research strongly depends on stimulus-responsive biomaterials because they enable researchers to develop new tissue engineering approaches and targeted medical interventions. These materials serve as important elements in multidisciplinary research because they enable biological process control, leading to new advancements in precise therapeutics and tissue regeneration.¹⁵²

Most of the studies investigate multiple biomedical applications of near-infrared (NIR)-activated smart carriers used for drug delivery systems, along with photothermal chemotherapy treatments. The carriers demonstrate multiple theranostics features that include pH-triggered drug discharge, together with therapy-targeting characteristics, combined with thermal-induced drug release and photothermal tumor removal. The deep-tissue penetration power of NIR light, alongside its heating mechanism, allows researchers to deliver drugs precisely and on demand to the desired cellular targets.¹⁵³

Various ongoing and emerging trends for the delivery of the targeted drugs through the blood–brain barrier, like ligand conjugation through biocarriers, passive transcytosis, membrane coating, and stimuli-triggered BBB disruption, provide diverse fields to date for further enhancements and upgrading technologies for the site-specific targeted drug delivery systems inside the brain.¹⁵⁴

Mesoporous silica nanoparticle (MSN) and NIR are famous for their role in drug targeting, photodynamic/photothermal therapy, and bio-imaging as diagnostic techniques, with the purpose of achieving a more holistic approach to treating carcinomas. This also highlights the role of various diverse combinational designing such as MSN–carbon-dots, MSNPersistent luminescence nanoparticles, MSN–graphenes/graphene oxide, MSN–fullerenes, MSN–carbon nanotubes, MSNQuantum dots, and MSN–metal nanoparticles, for future perspectives after overcoming current challenges of therapeutics (Fig. 18).¹⁵⁴

Fig. 18 Schematic illustration of the development of mesoporous silica nanoparticles (MSNs)-based hybrid nanotheranostics incorporating various diagnostic agents, including metal nanoparticles, quantum dots (QDs), carbon nanotubes (CNTs), fullerene (C60), graphene, graphene oxide (GO), persistent luminescence nanoparticles (PLNPs), and carbon dots (CDs). Reproduced with permission from ref. 154. © 2023 Elsevier. All rights reserved.

Due to the biocompatibility and targeting to the local area, high effectiveness towards the results of lipid nanoparticles, these are considered better therapeutics platforms for a variety of diseases like brain tumours.¹⁵⁵ The continual progress of NIR biosensors demonstrates remarkable potential to lead disease detection innovation and physiological assessment innovation in precision medicine settings.

6. Biocompatibility and biosafety assessment of NIR emitting biomaterials

NIR emissive aggregation-induced emission nanoparticles are increasingly being explored for biomedical applications due to their unique optical properties and potential for biocompatibility. The graphite-like carbon nitride (g-C₃N₄) based heterojunctions have spectacular merits in their affordability, insignificant toxicity, excellent stability, and high biocompatibility, making them very appealing to various biomedical applications. Rational design approaches and up-to-date advances of such nanomaterials in significant therapeutic and diagnostic applications, such as cancer treatment, antibacterial, wound healing, and biosensing, have been outlined. In addition, biosafety profiles and their possible toxic effects were well considered, which served as essential information on their clinical translation. The limitations regarding their optimization, scalability, and performance in vivo persist. Still, these gaps should be filled with the help of the quick progress in the field of material science and nanotechnology. With the recent explorations of strategies of functionalization and hybrid systems by the researchers, g-C₃N₄-based heterojunction can transform the biomedical fields and technologies.¹⁵⁶

Biomass-based hydrogels derived from plant origin are one of the successful varieties of biomaterials that have a chance to take place in biomedical spheres because of their low price, availability, and good biocompatibility. Regardless of their benefits, there is a significant difficulty in finding the perfect hydrogel that would be structurally and functionally close to the human tissues. A broad outline of several types of biomass-derived hydrogels, especially cellulose, hemicellulose, and lignin hydrogels, with their fabrication, characteristics, and tissue engineering, drug delivery, and wound healing applications being mentioned, has a wide range of applications. An analysis of biosafety and toxicity determinants is also provided, providing valuable information on whether they are appropriate to use in clinical settings. These barriers have to be broken with the help of further research efforts to increase the functional activity of biomass-based hydrogels.¹⁵⁷ The carbon-supported single-atom catalysts (SACs) are a unique platform in biomedical research applications, especially in association with cancer therapy in catalytic terms, because they are of nanoscale uniformity, high catalytic efficiency, non-toxicity, and biocompatibility. A detailed account of synthesis strategies and characterization methods that accurately engineer SACs in directed therapeutic undertaking. The general uniqueness of SACs has been experienced in treating cancer, antibacterial, biosensing, against oxidative stress, and sepsis treatment. Notably, the biosafety and toxicity analyses have been well conducted and made to confirm their clinical translatability. Despite considerable achievements, several problems remain, including mass production volume, stability in physiological conditions, and long-term biocompatibility. On balance, carbon-anchored SACs present an avenue of discovery in precision medicine, upon which interdisciplinary research will play a central role in fully realizing their potential in the biomedical real world.¹⁵⁸

In another example, the hemicellulose is a renewable and biodegradable lignocellulosic content with great potential for making numerous sustainable technologies in different sectors. Its availability, low cost, chemical modifiability, and environmental compatibility make it suitable for producing value-added products. The structural characteristics of hemicellulose-based materials, extraction, and characterization methods were systematically explained, and recent research in hemicellulose-based adsorbents, biomedical materials, energy, devices, sensors, and 3D printing, as well as food packaging, was described for its beneficial effects. Moreover, serious issues such as performance enhancement, scalability, and stability from a long-term perspective were investigated, which can provide points for future research. Although there are several technical and processing shortcomings, progress in the science and continued multidisciplinary research are likely to overcome such deficits. With the demand for sustainable products, hemicellulose-based products stand to contribute to sustainable development since the future has substantial potential in implementing nature-friendly products in the market soon.¹⁵⁹

7. Conclusion and future perspective

The evolution of second near-infrared (NIR-II) bioimaging has redefined the landscape of biomedical diagnostics and therapeutics by enabling deep-tissue visualization with high spatial resolution, low autofluorescence, and superior signal-to-noise ratios. Among the diverse array of nanomaterials explored for NIR-II applications, mesoporous silica nanoparticles (MSNs) have emerged as versatile platforms owing to their intrinsic advantages—such as high surface area, controllable pore size, excellent biocompatibility, and facile surface functionalization. The integration of luminescent coordination complexes, organic fluorophores, and metallic nanostructures into the MSN framework has enabled multifunctional capabilities for bioimaging, targeted drug delivery, and synergistic photothermal/photodynamic therapy, making MSNs highly attractive candidates for next-generation theranostic systems. Despite these promising attributes, several unresolved challenges continue to impede the clinical translation of MSN-based NIR-II platforms. Key limitations include insufficient colloidal and chemical stability in physiological environments, non-specific biodistribution, and uncertainty regarding long-term biocompatibility and clearance mechanisms. Moreover, while hybrid systems such as MSN–graphene oxide, MSN–fullerene, MSN-quantum dots, and MSN–metallic nanocomposites have demonstrated enhanced optical and therapeutic performance, most current studies lack a systematic understanding of their structure–property–biological response correlations. These gaps hinder the rational optimization of nanoplatforms for in vivo efficacy and safety.

Looking forward, future research must focus on precision surface engineering strategies to improve targeting efficiency, circulation time, and endosomal escape. Innovations in stimuli-responsive gatekeepers, biodegradable silica frameworks, and multi-modal imaging integrations are also essential to address current limitations. Furthermore, rigorous long-term in vivo studies, including pharmacokinetics, immunogenicity, and organ-level biodistribution, are urgently needed to facilitate regulatory approvals and clinical translation. The convergence of materials science, molecular biology, and translational nanomedicine will be pivotal in transforming MSN-based NIR-II systems from proof-of-concept designs into clinically viable tools for precision oncology and personalized medicine.

Conflicts of interest

There is no conflicts of interest.

Data availability

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

Acknowledgements

Abhineet Verma would like to acknowledge the Department of Chemistry, Malaviya National Institute of Technology (MNIT), Jaipur, for providing infrastructural facilities and financial support from the Faculty Seed Grant (FSG) MNIT. Special thanks to Prof. Satyen Saha (Department of Chemistry, BHU) for his valuable insight. Anurag Kumar Singh would like to acknowledge the Indian Council of Medical Research (ICMR), Department of Health Research, Ministry of Health and Family Welfare, Government of India, for support through the Research Associate (ICMR-RA) Award (No. 3/1/2/110Neuro/2019-NCD-I).

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