Harnessing light: Synthesis, mechanisms, and pre-clinical biomedical applications of stimuli-responsive multiscale composites

Abstract

Smart multiscale composites with stimuli-responsive versatility have significantly advanced the field of biomedical science by providing precise spatiotemporal control over modulating, diagnostic, and therapeutic functions. Light-responsive composite (LRC) systems, in particular, present unique advantages owing to their non-invasive nature, bio-favorable features, high accuracy, and capacity for real-time modulation. As a safe external stimulus, light can be manipulated to modify the chemical and biochemical behavior of material composites, thus offering considerable potential within the domain of photo-pharmacology. Consequently, researchers have developed multifunctional platforms for a broad spectrum of biomedical applications, ranging from bioimaging to wound healing, by integrating light-responsive components, such as photoinitiators, luminescent/plasmonic nanoparticles, polymers, hydrogels, and hybrid scaffolds, into composite systems. Despite the substantial proliferation of original research articles in recent years, there exists a notable deficiency in comprehensive frameworks or strategic blueprints that encompass these advancements. This timely review seeks to elucidate recent progress in the realm of LRC materials, with a focus on their design principles, activation mechanisms, and emerging applications within biomedicine. Herein, a variety of multidimensional composites are discussed, including two-/one-dimensional tissue engineering/phototherapeutic platforms and zero-dimensional molecular imaging agents. Nonetheless, the exploration of these varied light-responsive materials is articulated in a manner accessible to both general and expert audiences, ensuring clarity and comprehension of complex mechanisms. Furthermore, this review addresses the considerations and specific challenges pertinent to toxicity, reproducibility/scalability, as well as clinical transitions, contributing to a deeper understanding of the potential of these innovative material composites in practical applications.

Graphical abstract

1. Introduction

In the realm of clinical and pre-clinical research, composite materials have demonstrated considerable promise within the biomedical field. Recent innovations accentuate their role in bridging materials science with medicine, thereby providing customized platforms for theranostics, drug delivery, tissue engineering, and regenerative therapies [1,2]. These multiscale composites integrate reinforcing phases that encompass nanoscale and microscale within a cohesive matrix, leveraging hierarchical architectures to garner synergistic enhancements in mechanical integrity, functionality, and responsiveness [3]. The primary advantages of these composite materials encompass enhanced mechanical properties, extended biocompatibility, multifunctionality, controlled release capabilities, and stimuli responsiveness. Particularly, light-responsive composites (LRCs) have attracted substantial interest due to their potential to facilitate high-precision treatments and offer non-invasive localized therapeutic options [4]. It is important to emphasize that several key benefits arise from employing light as a functional element in the design of LRCs intended for biomedical applications [5]. Firstly, specific wavelengths of light can initiate the photo-induced structural change, thereby aiding in the construction of various stimuli-responsive drug delivery platforms. Secondly, light can be categorized into distinct wavelength ranges, which various biomaterials can independently manipulate to produce differential bio-inductive cues, thus influencing cell-material interactions. Thirdly, the intensity and duration of light exposure enable fine-tuning of the stimulation degree. Fourthly, light represents a physiologically less harmful method for modulating biomaterials when compared to variations in temperature or pH. Lastly, advanced optical instruments permit the confinement of light to predefined areas, enhancing the specificity of the therapeutic application.

Given the multifaceted features, numerous efforts have been directed toward the design and fabrication of various LRCs, over the years, spanning a wide range of dimensions from two-dimensional (2D) to zero-dimensional (0D) constructs [[6], [7], [8], [9], [10]]. Light-responsive material composites are characterized by their reaction to illumination, either during their formation into novel material species or when utilized as therapeutic platforms [[11], [12], [13]]. Relying on specific light-driven mechanisms, such as photoinduced phase transitions, photochemical reactions, localized surface plasmon resonance (LSPR), photothermal conversion, photoacoustic conversion, and photoelectric conversion, each dimensional category of composites has established its relevance across a myriad of biomedical applications. For instance, inorganic nanomaterials, particularly those of 2D and one-dimensional (1D) constructs, are being integrated with these polymers to develop bioactive hydrogel networks [14,15], phototherapy platforms [[16], [17], [18]], and anti-bacterial wound healing solutions [19,20]. The inclusion of optically active 2D/1D nanomaterials capitalizes on light to either induce therapeutic responses (such as photo-stimulated cellular modulation, tissue regeneration, photodynamic therapy, or photothermal therapy) [21] or to facilitate externally controlled drug delivery mechanisms (such as triggered release) [11,22]. Additionally, 0D materials emerge as promising candidates for molecular imaging applications (including fluorescence, photothermal, and photoacoustic imaging) due to their diminutive size, superior surface-to-volume ratio, and ease of synthesis [[23], [24], [25], [26]]. In many instances, two separate-dimensional materials composites are combined to facilitate multifunctionality and to positively modulate therapeutic efficacy. Significantly, the integration of multiscale materials in the formation of nanocomposites provides an opportunity for image-guided synergistic therapeutic functions [17,27,28], thus optimizing therapeutic strategies while minimizing the reliance on increased concentrations.

Inspired by the compelling scientific discoveries and substantial contributions of LRCs within the biomedical domain, this review aims to present a comprehensive overview of recent advancements in their applications (Fig. 1). The initial section will delineate various types of LRCs and their interactions with light energy. In contrast to existing literature reviews, this discussion will thoroughly elucidate the fundamental principles underlying the light-driven mechanisms associated with the development of new material composites and their photoactive applications. A critical examination of the necessity, advantages, and scope of various surface functionalization methods will also be conducted. Furthermore, significant applications of multiscale LRCs reported in recent literature will be meticulously reviewed, accompanied by authoritative perspectives. Finally, the predominant challenges, limitations, and potential bottlenecks in achieving successful clinical translation of these composites will be systematically identified and deliberated.

Fig. 1.

Schematic overview of different types of light-responsive materials composites, fundamental light-driven mechanisms, various surface functionalization strategies using bioactive components, and their potential biomedical applications, including molecular imaging, photo-active therapies, light-triggered drug release, and tissue engineering. D- Dimensional; (i) Photoinduced structural/phase transition; (ii) Photochemical reaction/photocatalysis; (iii) Localized surface plasmon; (iv) Photothermal conversion; (v) Photoacoustic conversion; (vi) Photoelectric conversion.

2. Types of multi-dimensional LRCs

Throughout the years, significant advancements have been made in the synthesis, construction, and fabrication of various multi-dimensional composite systems, encompassing 2D, 1D, and 0D materials. Each category of composite materials exhibits distinct characteristics, including high flexibility, enhanced surface areas, strong light absorption capabilities, and active surface features, which contribute to their diverse usability. Additionally, it is important to mention that there exists a notable overlap in the applicability of these multi-dimensional materials across various fields. In the following subsections, we provide a comprehensive analysis of different types of multi-dimensional materials and their structural features. Note that the authoritative perspectives/viewpoints following a critical examination of the applications of the representative LRCs are deliberated in Section 6.

2.1. 2D LRCs

The 2D LRCs exhibit significant advantages over bulk materials, particularly due to their enhanced surface-to-volume ratios and reduced dimensions along one axis. This characteristic enables size-dependent applications. Additionally, these materials, which primarily rely on graphene-based derivatives, molybdenum disulfide (MoS₂), Mxenes, and others, exhibit exceptional flexibility and mechanical strength, along with unique physicochemical and optical properties, which will be discussed in further detail in subsequent sections.

2.1.1. Graphene–based LRCs

Graphene/graphene oxide (GO)/reduced GO (rGO) are among the most extensively studied 2D materials, demonstrating exceptional potential across a broad spectrum of research areas [29,30]. Their unique physicochemical and electrical characteristics have underpinned significant advances in the design and development of therapeutic platforms [31]. One of key issue is that graphene-based materials exhibit limited light absorption and do not undergo phase transition process [32,33]; therefore, to attain certain light-responsive characteristics of these composites, GO, and rGO are frequently integrated with other functional optically-active polymers, such as azobenzene and polyaniline (PANI) and inorganic fluorescent NPs [[34], [35], [36]], thereby broadening their utility in optoelectronic applications within biomedical contexts. A noteworthy study by Teng et al. [6] detailed the synthesis of a 2D composite based on optically active GO and azobenzene-terminated polyhedral oligomeric silsesquioxane (Azo-POSS) (Fig. 2a). The preparation of this nanocomposite was straightforward, utilizing host/guest chemistry, which enabled the GO/POSS nanocomposite to exhibit reversible assembly and disassembly behavior upon exposure to specific light stimuli. Additionally, recent research by Yan and colleagues has demonstrated the application of photoelectric stimulation through rGO/g-C₃N₄/TiO₂ visible-LRCs, contributing to neural and osteoblastic differentiation [34]. Evidently, graphene derivatives are widely studied. Nevertheless, the large-scale production under Good Manufacturing Practice is another important direction that researchers should focus on to realize their quality abundance during desired pharmaceutical use.

Fig. 2.

Different types of 2D light-responsive composite materials. (a) Preparation of a light-responsive nanocomposite based on GO and azobenzene-terminated polyhedral oligomeric silsesquioxane (Azo-POSS). Reproduced with permission from Ref. [6]. Copyright 2019 Elsevier B.V. (b) Representative transmission electron microscopic (TEM) images of MoS₂-chitosan. Reproduced with permission from Ref. [39]. Copyright 2022 Elsevier B.V. (c) TEM image of 2D LRCs based on MoS₂ and GO. Reproduced with permission from Ref. [48]. Copyright 2018 Springer Nature Ltd. (d) LRCs based on MoS₂ and AuNPs. Reproduced with permission from Ref. [47]. Copyright 2025 Elsevier B.V. (e) Schematic illustration for constructing the Cu-TCPP/Ti₃C₂ 2D heterostructure nanocomposites. Reproduced with permission from Ref. [62]. Copyright 2023 Elsevier B.V. (f) Schematic showing the preparation of MXene-based nanocomposite hydrogel (top panel) and corresponding light-responsive phase change behavior (bottom panel). Reproduced with permission from Ref. [63]. Copyright 2024 Springer Nature Ltd.

2.1.2. MoS₂-based LRCs

MoS₂ is a prominent 2D material known for its tunable bandgap, strong light absorption, and large active surface area [37]. Its functional surface and ease of modification make it ideal for developing various light-responsive composites. These composites encompass a variety of configurations, including MoS₂-polymers [[38], [39], [40]], MoS₂-proteins [41,42], and MoS₂-other inorganic nanostructures [[43], [44], [45], [46], [47], [48]], which are predominantly employed in biomedical research. For instance, recent work by Cao et al. [39] describes the synthesis of a nanocomposite primarily composed of 2D MoS₂ nanosheets and chitosan (Fig. 2b), wherein the individual components are chemically linked, leading to a stable nanocomposite. However, there is a noted inadequacy in the detailed demonstration of the morphological and structural features, as well as the uniformity of the nanocomposites. In another investigation, Liu and colleagues reported the synthesis of 2D composites utilizing MoS₂ nanosheets in conjunction with GO (Fig. 2c) [48]. The inclusion of GO is aimed at enhancing aqueous dispersity due to the presence of hydroxyl groups on its surface. Nonetheless, the method employed for composite formation, which involved simple mixing of MoS₂ nanosheets with GO, raises concerns regarding long-term stability in biological environments. Thus, a thorough analysis of the reported composite is warranted. Additionally, recent contributions from a research group led by Feteixa and colleagues have advanced the field with the development of a 2D MoS₂/gold NPs (AuNPs) composite [47]. This innovative research employed a one-step approach utilizing ultrasound-assisted liquid-phase exfoliation to fabricate the composite, resulting in distinct morphological characteristics. Notably, the functional nanocomposites exhibited well-distributed and firmly attached AuNPs, as evidenced by TEM analyses (Fig. 2d). MoS₂ is well-known for its versatile physicochemical properties, making it a promising candidate for pharmaceutical applications. However, several critical challenges need to be addressed to facilitate its clinical use. These challenges include achieving a uniform particle size distribution, maintaining precise and reproducible layer structures, and minimizing defect densities that could compromise its functional performance. Furthermore, comprehensive long-term and cyclic photostability assessments are necessary to verify its durability and reliability under physiological conditions.

2.1.3. MXene-based LRCs

Transition metal nitrides, oxycarbides, and carbides, collectively referred to as MXenes, have emerged as a significant class of 2D nanomaterials characterized by exceptional properties such as high hydrophilicity, chemical and thermal stability, electrical conductivity, and inherent biocompatibility [49]. MXenes and their LRCs highly valuable in biomedical therapeutic applications as they exhibit diverse surface chemistry [50], high mechanical strength [51], and superior NIR responsiveness [52]. Despite their inherent advantages, the practical application of MXenes is often hindered by undesired agglomeration in certain matrices [53], posing challenges in achieving optimal performance in various biomedical contexts. To address this limitation, MXenes are frequently hybridized with active polymers or other nanostructured materials, facilitating the fabrication of functional composites [53,54]. Importantly, the conjugation of individual materials also add additional functionalities, such as targeting capabilities, enhanced colloidal stability, and improved physicochemical characteristics, therefore, utilized in wide range of applications [[55], [56], [57], [58]]. Recent developments indicate a notable increase in the exploration of innovative MXene-based LRCs, driven by their unique characteristics [[58], [59], [60], [61]]. For instance, Zhang et al. [20], developed a complex nanocomposite hydrogel based on MXene (Ti₃C₂Tx) in combination with poly(vinyl) alcohol, chitosan, and metal-organic frameworks (MOF). The resulting hydrogel LRCs demonstrated potential for stimuli-responsive drug delivery and wound healing applications. In a separate investigation, Li and colleagues utilized Ti₃C₂Tx MXene to fabricate composites that also involve MOF (Fig. 2e) [62], aiming to enhance photocatalytic performance through an interface engineering strategy. This enhanced photocatalytic function could be effectively utilized in the generation of free radicals, thereby advancing applications in wound healing and bacterial eradication. Additionally, another noteworthy light-responsive MXenegel was reported by Chen's group, which involved the preparation of a composite using MXene and azobenzene (Fig. 2f; top panel) [63]. The incorporation of phase change materials, such as azobenzene, allows the MXenegels to undergo a reversible sol-gel transition upon exposure to UV and visible light (Fig. 2f; bottom panel). The versatility of MXenes in creating unique LRCs is impressive. However, MXene-based composites encounter significant challenges related to oxidative stability, biocompatibility, and scalable synthesis, which hinder their clinical application in biomedicine. For example, MXenes, particularly Ti₃C₂T_x, tend to oxidize quickly in aqueous and physiological environments. This oxidation results in a loss of conductivity and diminishes their photothermal performance.

2.1.4. Other emerging 2D LRCs

In addition to the previously discussed 2D LRCs, various alternative candidates demonstrate significant potential within biomedical applications. These candidates include, but are not limited to, molybdenum dioxide (MoO₂) [64], graphitic carbon nitride (g-C₂N₄) [65], and niobium diselenide (NbSe₂) [66]. A study conducted by Sun et al. [64] reported the synthesis of a composite hydrogel that integrates 2D MoO₂, laponite, and poly(N-isopropylacrylamide) (PNIPAM). According to their findings, these newly synthesized composites exhibit comparable NIR responsiveness to that of GO and MXene hydrogels, while simultaneously demonstrating enhanced optical transmission. Recently, Khoshtabiat and colleagues developed a hybrid nanocomposite containing functional components such as g-C₃N₄, CaO₂, Fe₃O₄, among others [65]. However, the complexity of this nanocomposite, comprising multiple components, poses challenges to its practical applicability, as major clinical platforms require simplistic yet effective formulations to address various biomedical concerns. We opine that researchers should prioritize the development of more straightforward designs of 2D LRCs centered on g-C₃N₄. Moreover, Zhong's research group has made significant strides in designing simple LRCs utilizing short peptides and PEGylated NbSe₂ nanosheets [66]. Under NIR light exposure, these hydrogel composites undergo conformational changes, resulting in the release of encapsulated cargo. This concept parallels the innovative approaches in which azobenzene serves as a gatekeeper to facilitate the offloading of drug molecules from the primary composite structures comprised of either polymeric or inorganic nanomaterials.

2.2. 1D LRCs

A distinctive characteristic of 1D nanostructures is their diminished dimensionality and elevated aspect ratio, which facilitates the efficient transport of electrical carriers along a controlled direction, rendering them highly suitable for charge transport within integrated nanoscale systems. The strategic incorporation of light-responsive 1D nanomaterials into polymeric or hybrid nanocomposites is intended to leverage remote activation, achieve precise control, and enhance multifunctionality. Such materials can be employed for both diagnostic purposes and clinical or nonclinical nanotherapeutics.

2.2.1. Gold nanorod (AuNR)-polymer LRCs

The gold nanorod (AuNR)–polymer nanocomposites serve as promising biomedical materials due to their tunable LSPR, which can be adjusted through aspect ratio control [[67], [68], [69]]. This tunability facilitates efficient absorption and scattering of light in the NIR region, which is advantageous as it minimizes damage to surrounding biological tissues. Furthermore, the interaction of incident light with the AuNRs induces localized heating through non-radiative relaxation of excited electron states (described in Section 4), thereby enabling precise therapeutic interventions. When situated within composite structures, AuNRs are typically embedded in biocompatible component matrices, which enhances their stability and dispersibility and improves their targeting efficacy in biological environments. Duman et al. [70] contributed significantly to the field by formulating a nanocomposite that integrates AuNRs with the cationic porphyrin TMPyp alongside polyacrylic acid (PAA) (Fig. 3a). The LRCs were established through the electrostatic attachment of the oppositely charged components. Despite the straightforward design and fabrication processes employed, the stability and durability of these composites within the rigid biological milieu necessitate further validation to ensure their suitability for clinical applications. Moreover, it has been observed that the implementation of facile strategies that circumvent multi-step synthesis routes in the development of AuNR-based nanocomposites remains a critical challenge. To address this issue, Lin et al. [71] reported the synthesis of nanocomposite hydrogels centered on AuNRs (Fig. 3b). This was achieved through cross-linking with PNIPAM. The final composites were synthesized via the polymerization of NIPAM using N,N′-bis(acryloyl)cystamine (BACA)-modified AuNRs as crosslinkers. The BACA moiety contains a disulfide bond within its structure, facilitating the formation of dynamic and reversible Au-thiolate bonds by directly mixing AuNRs with BACA, thus allowing for the efficient preparation of AuNR crosslinkers prior to hydrogel synthesis. In our assessment, the cross-linking approach employed is anticipated to enhance the stability and reliability of the resulting hydrogels in biological environments. A crucial factor for the scalable production of AuNRs in pharmaceuticals is the need for careful and precise control of their aspect ratio. This control is essential for tuning their plasmonic properties, which are necessary for specific therapeutic applications. Additionally, integrating AuNRs into polymers involves multi-step preparation methods. Therefore, in-situ synthesis of these LRCs could be vital in accelerating their advancement in clinical research.

Fig. 3.

Different types of 1D light-responsive composite materials. (a) Schematic illustration of LRCs incorporating mainly AuNRs, cationic porphyrin TMPyP (5,10,15,20-tetrakis(1- methyl 4-pyridinio)porphyrin tetra(p-toluene sulfonate)), and polyacrylic acid (PAA). Reproduced with permission from Ref. [70]. Copyright 2020 Royal Society of Chemistry. (b) Preparation of hydrogel composite based on light-responsive AuNRs and Poly(N-isopropylacrylamide) (PNIPAM). Reproduced with permission from Ref. [71]. Copyright 2021 Springer Nature Ltd. (c) Schematic of an LRC based on carbon nanotube (CNT) and pyrrolidonecarboxylic acid zinc sponge. Reproduced with permission from Ref. [76]. Copyright 2025 Elsevier B.V. (d) Construction of CNTs/carbon dots (CDs)/PNIPAM and CNTs/CDs-PAA nanocomposites. Reproduced with permission from Ref. [79]. Copyright 2024 Elsevier B.V. (e) Scanning electron microscopic (SEM) image of PANI/GO NIR-responsive nanocomposite prepared via physical cross-linking. Reproduced with permission from Ref. [35]. Copyright 2019 Elsevier B.V. (f) SEM image of LRCs based on poly(3-hexylthiophene), polycaprolactone, and poly-pyrrole. Reproduced with permission from Ref. [14]. Copyright 2022 Elsevier B.V.

2.2.2. Carbon nanotube (CNT)-light-responsive polymers

Carbon-based materials, especially CNTs, are valued for their exceptional mechanical, optical, and electrical properties [72]. When combined with polymer fibers, they form light-responsive nanocomposites suited for biomedical use [73]. These hybrid materials support synergistic cancer therapies by co-delivering therapeutic and imaging agents [74], and in tissue engineering, CNTs enhance structural support and cellular interactions for improved regeneration [75,76]. Recently, Gwyther and colleagues reported the preparation of semiconducting CNTs conjugated with green fluorescent protein (GFP) via genetically encoded phenyl azide photochemistry [77]. This innovative composite was utilized to develop bio-phototransistors, which hold potential for further application in light-driven bioimaging technologies. In another interesting work, Oh et al. [78] developed a unique nanocomposite comprising CNTs and monodomain liquid crystal elastomers (MLCEs). This composite exhibited light-induced dynamic exchange reactions as well as light-triggered actuation capabilities. The multi-walled carbon nanotubes (MWCNTs) were effectively dispersed within the MLCE matrix utilizing a newly synthesized amphiphilic dispersant, poly(4-cyanobiphenyl-4′-oxyundecylacrylate-co-pyrene methyl acrylate). The dispersant demonstrated π-π interactions with the MWCNT fillers, attributable to the pyrene moieties, as well as favorable miscibility with the MLCE matrix, due to the cyanobiphenyl mesogenic moieties. The distinctive photoactuation properties of CNT-MLCE composites suggest their significant potential in enabling precise and remote manipulation of cellular processes, including ion channel modulation, cell signaling pathways, and cellular distribution. Furthermore, a recent study led by Zhai's group reported the development of a nanocomposite scaffold based on CNTs cross-linked with pyrrolidonecarboxylic acid, zinc, and a decellularized dermal matrix (Fig. 3c) [76]. This particular scaffold exhibited several photo-responsive properties, including a noteworthy photo-detachable behavior associated with the CNTs. The prevalence of nanostructures featuring photo-detachable characteristics represents a subclass of stimuli-responsive materials currently being leveraged for cargo release applications, such as drug delivery. This approach allows for spatiotemporal precision, non-invasive activation, and a reduction in premature drug release. Importantly, photo-detachable LRCs can be engineered to respond to specific wavelengths or intensities of light, thereby offering customizable solutions for diverse clinical scenarios. The preparation of stimuli-responsive CNT-based nanocomposites is typically achieved via covalent bonding with polymers. However, the pretreatment of CNTs prior to this bonding can alter their surface structure, which may detrimentally affect their intrinsic optical and other properties. To mitigate this issue, Wang and colleagues proposed a simple and non-destructive activation method [79]. In their approach, CNTs were initially activated using carbonaceous materials such as carbon dots (CDs) through π-π interactions. Subsequent conjugation of various polymers, including PNIPAM and PAA, with the CNTs-CDs led to the formation of stable nanocomposites (Fig. 3d).

2.2.3. Conducting/semiconducting polymer nanowire/nanofiber-based LRCs

Conducting and semiconducting polymers have advanced smart LRCs due to their unique optoelectronic properties [80]. The 1D polymer nanowires/nanofibers offer light sensing, strong fluorescence, low cytotoxicity, high photostability, ROS generation, and photothermal/photoelectric effects [[81], [82], [83]], with versatile design and easy functionalization supporting biomedical use. Upon review of existing studies, it is evident that the 1D polymer composites responsive to light predominantly utilize PANI [35,84] and poly(3-hexylthiophene) (P3HT) [14,15,85,86] as their foundational materials. Notably, a study conducted by Wei et al. [35] investigated the development of an NIR-responsive nanocomposite utilizing PANI and GO (Fig. 3e). Their findings demonstrated that the PANI nanofibers were successfully conjugated with GO through a process of physical cross-linking. Although a homogeneous dispersion of PANI on the GO surface was reported, the fibrous characteristics of PANI remain somewhat ambiguous, highlighting the necessity for a meticulous preparation process. Conversely, Waqas and associates employed a nozzle-free electrospinning technique to fabricate PANI-polyvinylpyrrolidone (PVP) nanofiber composites, claiming to present this straightforward approach for the first time [87]. Evidently, PANI is a well-researched conducting polymer, yet its nanocomposites responsive to different optical energies remain underexplored. This presents opportunities for future research in areas like photothermal tissue integration and light-controlled cellular behavior in tissue regeneration.

Similarly, P3HT-based conductive polymer composites have garnered significant attention in recent years as light-responsive alternatives in the biomedical arena. For example, a research group led by Zhang reported the dynamic gelation of conductive 1D polymer nanocomposites based on P3HT and ZnO nanowires via a sol-gel process [15]. It is noticed that, in the field of healthcare monitoring systems, such as point-of-care wearable diagnostic tools, there is a growing demand for biomedical devices that mimic soft tissue while maintaining high elasticity [88]. The flexibility and soft texture of P3HT nanofibers have been identified as optimal for achieving these objectives. Mao et al. [86] reported the preparation of light-absorbing composite materials primarily based on P3HT and filler components such as phenyl-C61-butyric acid methyl ester (PCBM) and polystyrene-isoprene-styrene (SIS). In their research, the influence of PCBM and SIS on the morphology of P3HT nanowires was observed. For instance, the use of SIS yielded nanowires with high aspect ratios and enhanced stretchability; however, the detailed mechanisms underlying these phenomena remain unexplored. Another notable contribution was made by Yuan and co-workers, who prepared LRCs comprising P3HT, poly(caprolactone) (PCL), and polypyrene (PPY) (Fig. 3f) [14]. This multicomponent system was obtained through a multi-step preparation process, beginning with the electrospinning of P3HT/PCL followed by the subsequent polymerization of PPY. Notably, this tri-polymer nanocomposite exhibited distinct fibrous morphology and smooth surface characteristics, setting it apart from previously discussed nanofibers (Fig. 3e). Given the high photoelectric conversion capacities of P3HT [89], it is anticipated that such materials could find utility in photo-stimulating applications within tissue engineering. It has been noted that numerous novel LRCs relying on 1D nanofibers have been reported. However, most of these studies did not report on their long-term photostability, which is necessary for chronic or cyclic therapies. Furthermore, some polymers, such as PPy, may trigger immune responses; therefore, thorough investigations into their biological interactions are necessary.

2.3. 0D LRCs

The 0D LRCs constitute a category of advanced materials that leverage the distinctive characteristics of nanostructured materials with dimensions less than 200 nm, such as quantum dots, and other small-sized NPs. These 0D nanomaterials, characterized by confinement in all three spatial dimensions, exhibit quantum confinement effects that facilitate tunable optical and electronic properties. In contrast to materials with larger dimensions, such as those in 2D/1D categories, 0D nanomaterials possess an enhanced surface-to-volume ratio, enabling extensive modifications to their surfaces. Incorporating 0D NPs into polymer matrices or composites allows materials to alter their properties, like fluorescence, photothermal response, and structural conformation, when exposed to specific light wavelengths or intensities. In biomedical applications, LRCs utilizing these NPs show promising potential for various applications.

2.3.1. Graphene quantum dot (QD)-based LRCs

The GQDs are emerging 0D materials with high dispersibility, chemical/thermal stability, biocompatibility, and tunable photoluminescence [[90], [91], [92]]. Additionally, their active surface groups enable integration into composite systems [93], and their sub-10 nm size allows effective imaging and targeted therapy by overcoming biological barriers [94]. Our observations indicate that GQDs can be effectively incorporated into various structures, including small/large polymer matrices [[95], [96], [97], [98], [99]], metallic compounds [23,[100], [101], [102]], liposomal systems [103], and other nanomaterials [104,105] to form desired LRCs. Recently, Kumara et al. [99] made a notable contribution in the related field by creating a novel composite platform based on GQD-polyethylene imine/chitosan (Fig. 4a). However, the preparation of these LRCs involves complex and time-consuming experimental processes, and the resulting products demonstrated substantial aggregation (Fig. 4b). In our anticipation, the relatively low surface potential attributed to the hybrid polymer constituents may influence the homogeneous dispersion of these newly developed composite systems. Furthermore, Divband's research group has reported a composite system incorporating GQDs with metallic NPs [102]. Their recent findings indicate that GQDs were successfully integrated with iron oxide NPs to form a robust LRC. Nevertheless, observations indicated that this nanocomposite system exhibited some degree of aggregation, which could restrict its application in potential biomedical fields. In contrast, Ramedani et al. [103] presented LRCs based on GQDs and a poly(vinylidene fluoride-trifluoroethylene) liposomal system. Notably, the particles within this nanocomposite exhibited distinct homogeneity and a lack of aggregation when analyzed under electron microscopy (Fig. 4c). Such nanocomposites, characterized by a low polydispersity index, are particularly sought after in nanomedicine research due to their promising attributes. Looking forward, the development of GQD-based LRCs is far from exhaustive, as their functional surfaces can be conjugated or incorporated with a variety of other nanostructures, including MXenes and MoS₂, among others.

Fig. 4.

Different types of 0D light-responsive composite (LRC) materials. (a) Schematic illustration showing the complex preparation route of LRCs based on GQDs conjugated with other functional components such as polyethylene imine and chitosan. (b) Representative transmission electron microscopic (TEM) image. Reproduced with permission from Ref. [99]. Copyright 2022 Elsevier B.V. (c) Field-emission scanning electron microscopic image. Reproduced with permission from Ref. [103]. Copyright 2022 Elsevier B.V. (d) Schematic diagram of the complex nanocomposite system based on ZnCdSe/ZnS QDs, Fe₃O₄ (IO), and polymers. Reproduced with permission from Ref. [113]. Copyright 2023 Elsevier B.V. (e) TEM image of LRCs utilizing g-C₃N₄ QDs and carbon-based nanostructures. Reproduced with permission from Ref. [8]. Copyright 2020, Elsevier B.V. (f) TEM image of AuBy@ZIF-8(CV)@PMA LRCs. Inset: the colloidal stability of the NCs in the absence and presence of the polymer component. Reproduced with permission from Ref. [136]. Copyright 2024 Wiley-VCH GmbH. (g) Schematic of a nanocomposite pErNP–OVA–CpG B (OVA proteins were conjugated to the NH₂-groups on pErNP-P³ via EDC chemistry and then mixed with CpG B for electrostatic complexation to form the pErNP–OVA–CpG B nanocomplex). Reproduced with permission from Ref. [140]. Copyright 2023 Springer Nature Ltd.

2.3.2. Semiconductor QD-based LRCs

Semiconductor QDs, both traditional and non-traditional, have attracted attention for their strong photoluminescence driven by quantum confinement [106,107]. The LRCs incorporating traditional QDs include cadmium telluride (CdTe), cadmium sulfide (CdS), cadmium selenide (CdSe), zinc sulfide (ZnS), and indium phosphide (InP) [[108], [109], [110], [111], [112]]. A notable study by Chen et al. [113] reported the development of a nanocomposite platform that integrates ZnCdSe/ZnS traditional QDs with iron oxide (Fe₃O₄) through a one-pot synthesis approach (Fig. 4d). In our opinion, this design strategy facilitates the control of nanocomposite directionality for precise targeting, while the magnetic-driven aggregation of LRCs is anticipated to enhance signal strength in bioimaging applications. In a concurrent investigation, Lia and co-workers introduced a core@shell nanocomposite system comprising CdTe@Cds and TiO₂ [109], demonstrating that these LRCs possess a broad absorption spectrum in the visible light range. Despite their abundance in forming bioactive nanocomposite materials, the individual traditional QDs are known to exhibit inherent toxicity and other critical issues [114], prompting researchers worldwide to explore alternative solutions. Among the most nontraditional semiconductors, g-C₃N₄ and MoS₂-based LRCs have been reported to be the predominant ones [8,[115], [116], [117], [118], [119], [120]]. The primary advantages of these nontraditional QDs, g-C₃N₄–for instance, include a relatively high level of biocompatibility and the ability to be excited using NIR excitation sources [121]. Notably, these nontraditional QDs demonstrate physicochemical properties, including photocatalytic effects, photodynamic, and photothermal characteristics, as well as anti-inflammatory effects, all of which are essential for various biomedical applications [122]. Recently, Liu et al. [8] presented a rationally designed LRC system utilizing g-C₃N₄ and carbon nanostructures (Fig. 4e), which demonstrated not only photothermal effects but also significant capacity for drug payloads, enabling synergetic treatment modalities such as combined photothermal and chemotherapy. Interestingly, the superior physicochemical properties of g-C₃N₄ have led to its conjugation with traditional QDs to further enhance quantum efficiencies. For instance, Du and colleagues developed a composite structure combining CdS with g-C₃N₄ and potassium persulfate, reporting an enhancement of quantum efficiency at least 18.4 times greater than that of individual or other composite counterparts [116]. From our perspective, this fundamental research is crucial for the evolution of composite nanosystems, ensuring global resource management, minimizing therapeutic dosages, and reducing toxicity to biological systems. In terms of other non-traditional QDs, the application of MoS₂ in functional nanocomposites was demonstrated in a significant study by Pandey and associates, who synthesized a bioactive LRC system using MoS₂ and DNA-based hydrogel [118]. This one-pot synthesis strategy not only conserves time but also yields a biologically active surface conducive to multiple drug delivery systems, addressing the challenges of undesired and unpredictable clearance of NPs. In our understanding, the advancements in the design strategies of composite systems based on QDs, regardless of their type and functions, are evident. Also, it is important to note that the toxicities of elements used in forming QDs are perhaps the major bottleneck for their utilization in real-life applications. Therefore, the future exploration of novel fluorescent QDs (traditional or nontraditional), should focus on realizing the safe and efficient nanosystems intended for biomedical use. Moreover, the study of long-term physiological stability of QDs-based LRCs may provide a in-depth understanding of their biological adaptability.

2.3.3. Metal nanoparticle-based LRCs

The significant interest in metal NPs can be attributed to their remarkable longevity and efficacy as advanced nanoplatforms within the realm of biomedical applications [123]. Metal NP composites integrate the distinctive properties of various metals (such as gold (Au), silver (Ag), copper (Cu), calcium (Ca), and rare earth elements (e.g., cerium, Ce)) with a surrounding matrix, which may consist of polymers or other organic and inorganic components. Generally, metal NPs are characterized by their strong plasmonic effects or catalytic properties [[124], [125], [126]] when subjected to specific light absorption conditions, making them crucial components in LRCs. For instance, Au-based NPs are extensively utilized in photothermal therapy for cancer treatment [28], while ceria-based formulations have demonstrated efficacy in antioxidant-mediated wound healing applications [[127], [128], [129], [130]]. Given the widespread popularity of noble metals, the prominence of noble metals, particularly in the realm of LRCs based on Au and Ag, is particularly notable in plasmon-derived photothermal therapies and tissue engineering [20,27,[131], [132], [133], [134], [135], [136], [137]]. Notably, Cedrún-Morales et al. [136] developed an LRC integrating AuNPs into a MOF matrix, resulting in core-shell structures (Fig. 4f). Also, they tried to solve the colloidal stability issues that several inorganic nanomaterials possess by additional incorporation with a polymer component (as depicted in the inset of Fig. 4f). Though the aforementioned LRCs encompass multiple elemental constituents, further investigation into their long-term structural integrity in biological environments is warranted, especially considering the potential effects of the low pH tumor microenvironment on such complex structures when utilized in photothermal experiments. Moreover, cerium-based materials have gained momentum in biomedical research, evidenced by significant contributions from Huang's group, which designed a NIR light-responsive nanomotor composite reliant on Ce-doped mesoporous silica and Au NPs [130]. These innovative constructs not only exhibit therapeutic properties but also demonstrate NIR-triggered propelling capabilities, facilitating guided therapy applications. In another important study, Zheng et al. [138] further explored this domain by combining ceria NPs with gelatin to create an effective photothermal composite agent. Over the decades, the incorporation of rare-earth metals into various biomedical applications has significantly advanced fields such as deep tissue imaging, biosensing, cancer theranostics, and wound healing [32,[139], [140], [141]]. In an excellent research investigation led by Dai's group, a smart LRC platform was developed based on rare-earth UCNPs combined with polymer, proteins, and biomaterials matrices (Fig. 4g) [140]. This smart nanocomposite platform offers numerous advantages, including in vivo tracking, cancer nanovaccines, and the capacity to elicit immune responses, establishing it as an ideal candidate for a range of synergistic biomedical applications. It is important to note that, while UCNPs possess multiple benefits, including biocompatibility, they are susceptible to significant colloidal aggregation owing to hydrophobic interactions, van der Waals forces, and various interaction forces at different concentrations [[142], [143], [144]]. The combination of polymers and bioactive components, as demonstrated in Dai's research, has the potential to mitigate these internal challenges. It is anticipated that the versatility and significance of metal NPs will remain unchallenged by emerging new materials, ensuring their continued prominence as crucial components in the development of multifunctional bioactive LRCs.

3. Reproducibility and scalability of multiscale LRCs

In real-life applications, reproducibility and scalability of multidimensional composites present significant challenges. It is crucial to achieve consistent results and enable large-scale production, necessitating stringent control over synthesis parameters and the associated properties of the materials involved. Critical issues arise from the intrinsic variability associated with individual material classes, such as 2D, 1D, and 0D, as well as the requirement for innovative techniques to effectively integrate these materials into composites without compromising their distinct properties. It has been realized that for 2D and 0D composites, techniques such as hydrothermal synthesis, microwave-assisted synthesis, and thermal decomposition offer a favorable combination of control, efficiency, and scalability. Conversely, for 1D composites, preferred methods include electrospinning, the sol-gel process, hot pressing, and carbonization techniques, which are well-regarded for their effectiveness in producing high-quality materials.

4. Light-driven mechanisms

As emphasized earlier, light-sensitive/responsive materials and their composites exhibit distinct functionalities under specific optical illuminations. These functionalities encompass a variety of processes, including structural and phase transitions, the initiation of photochemical reactions, the release of photothermal energy, and the capacity for photoelectric conversion. Materials that undergo structural changes, such as azobenzene, hold significant potential for applications in controlled drug release for wound healing. Conversely, composite materials that incorporate MoS₂ and MXenes demonstrate the ability to generate ROS upon exposure to light, thus enhancing precision therapies through targeted treatment approaches. The subsequent subsections will provide an in-depth exploration of the mechanisms underlying the representative light-responsive materials and composites.

4.1. Photoinduced phase transition mechanism

Photoinduced materials, which exhibit structural changes and phase transitions, serve as critical components in LRCs. These materials include photo-active polymers such azobenzene compounds and various phase-changing materials (PCMs). As per published literature, the photoisomerization mechanism is attributed to the design of inorganic LRCs, in which azobenzene polymers serve as photo-active components [145]. Specifically, the azo chromophore isomerizes by illumination with UV light (300–400 nm) from the stable linear ‘trans’ form to the bent ‘cis’ form, whereas reverse isomerization can be triggered by irradiation with visible light (425–500 nm) (Fig. 5a). Recently, a significant advancement in the realm of photo-responsive materials has been observed with the integration of PCMs into nanocomposite platforms. PCMs possess the unique capability to undergo transitions between different physical states (e.g., from solid to liquid and vice versa) in response to specific wavelengths of light. This property enables the tuning of optical and other relevant characteristics within the framework of LRC systems. The underlying mechanism of PCMs involves the interaction of incident light with a defined molecular architecture that triggers a phase transition, thereby allowing these materials to effectively store or release thermal energy upon exposure to optical energy, as illustrated in Fig. 5b. Intriguingly, the transition from solid to liquid and vice versa would enable stimulus-controlled drug delivery [131], whereas the release of thermal energy would impart photothermal characteristics [146]. Notably, photo-active molecules such as azobenzene, cyclodextrin, and certain esters can be employed in conjunction with desired hydrogel compounds to formulate effective PCMs [11,147,148].

Fig. 5.

Different light-driven mechanisms, observed in different light-responsive components. (a) Photoinduced structural change in azobenzene via reversible photoisomerization under exposure to UV and Visible light. (b) Schematic illustration showing the mechanism of representative light-responsive phase-changing materials undergoing phase transition, which is ultimately realized through stimulus-controlled drug release and photothermal properties. (c) Mechanism of ROS generated by various photocatalytic materials via reduction and oxidation steps of oxygen and water. (d) The polarization of charge carriers in metal nanoparticles when exposed to the electromagnetic spectrum. (e) Schematic illustration of the localized surface plasmon resonance (LSPR)-driven heat dissipation in metal nanoparticles and 2D MXenes comprising metallic components. (f) Plasmon-induced ROS generation ability in MXenes. (g) Schematic overview of photothermal effects on metal and non-metal nanostructures used in LRCs. The excitation source can be varied depending on the nanomaterials. (h) Mechanism of photoacoustic (PA) signal emission from a representative nanomaterial after exposure to pulsed and modulated light. The PA signal generation in metal and non-metal can be attributed to thermal expansion caused by surface plasmon and non-radiative energy transfer mechanisms. (i) Photoelectric conversion mechanism: upon excitation with light, the excitation is created in conducting/semiconducting materials, which are driven apart as free charge carriers, thus giving rise to a photocurrent. (j) Photo-induced charge transfer mechanism in P3HT polymer-based heterojunction with PCBM or carbon nanotubes (CNT).

4.2. Photochemical reaction (photocatalysis) mechanism

Photochemical reactions, particularly those associated with photocatalytic effects, have emerged as critical mechanisms in a range of biomedical applications that leverage LRCs. The functional photo-active material components, such as MoS₂, MXenes, ceria, carbon-based nanostructures, and other NPs, exhibit pronounced photocatalytic properties [[149], [150], [151]]. These photocatalytic characteristics are frequently employed in the generation of ROS, which serve various therapeutic purposes, including photochemical tissue bonding for wound healing, as well as photodynamic therapy for antibacterial, anti-inflammatory, and anti-cancer applications. Furthermore, the photocatalytic properties in combination with other optical properties also support fluorescence and photoacoustic imaging, especially when paired with other nanomaterials [152]. Given the necessity of understanding the accurate and comprehensive concept, a systematic analysis of the mechanisms by which light-activated ROS are generated from these materials is warranted. According to established mechanisms, most photocatalytic materials can absorb light through electromagnetic spectrum, thereby generating electron-hole pairs (i.e., excitons). These electron-hole pairs subsequently interact with molecular oxygen and water present in the biological milieu to produce various ROS, including singlet oxygen, superoxide free radicals, and hydroxyl free radicals. Note that the efficacy of ROS generation through photocatalysis relies on several critical factors, including the optoelectronic band structure, charge-carrier dynamics, and nanoscale morphology and surface properties of the nanocomposite materials [[153], [154], [155]]. Notably, emerging photocatalytic materials, such as MXenes, are capable of generating ROS through two distinct pathways: the light-triggered electron-hole pair mechanism (Fig. 5c) and the LSPR (discussed in Section 4.3) induced by their metallic constituents [156]. Ultimately, the ROS generated from these photocatalytic processes induces oxidative stress that can mediate target cell death, particularly in cancer or other treatment areas. It is also important to highlight that photocatalytic activity may facilitate the light-induced degradation of polymeric coatings or linkers within nanocomposites [157,158], thereby enabling on-demand drug release at targeted sites. This capability is especially advantageous in tumor microenvironments, where precise therapeutic control is essential.

4.3. Localized surface plasmon mechanism

LSPR, also generally known as surface plasmon, is a prominent optical phenomenon uniquely associated with metals and their nanocomposites. This phenomenon occurs when light of a specific wavelength interacts with metallic NPs, leading to the collective oscillation of their free electrons and holes at a designated frequency (Fig. 5d). The resultant resonance enhances both the absorption and scattering of light, generating a robust, localized electromagnetic field. In metal-based composites, LSPR serves as a critical mechanism for photothermal temperature enhancement and the generation of ROS. The production of thermal energy through LSPR in metal NPs and 2D MXene materials is illustrated in the accompanying diagrams (Fig. 5e) [52]. Under resonant light illumination, typically optimized within the NIR spectrum for effective deep tissue penetration, LSPR excitation induces intense local electromagnetic fields. These “hot” electrons undergo non-radiative (i.e., thermal) relaxation processes; initially transferring energy to the nanocrystal lattice through electron-phonon coupling, followed by energy dissipation to the surrounding medium via phonon-phonon interactions, ultimately manifesting as heat. It is noteworthy that the plasmon-induced photothermal conversion efficiency (PCE) is contingent upon the physicochemical properties of the materials involved [159]. For instance, nanocomposites composed of metal nanostructures particularly of noble metals or MXenes, with large absorption cross-sections, have been demonstrated to achieve higher PCE, thereby enhancing their applicability in various biomedical applications. Conversely, LSPR also plays a pivotal role in facilitating the production of ROS in nanocomposites containing metallic elements (e.g., MXenes) through plasmonic thermalization [160]. Specifically, when MXenes are excited via a particular light (e.g., NIR), the plasmonic hot carriers (such as hot electrons) are generated and accumulated on the surface, which directly reduce molecular oxygen to superoxide free radicals, thereby imparting ROS generation activity (Fig. 5f) [161]. From our perspective, combining these functional materials into LRCs can endow them with superior therapeutic capabilities in addressing various biomedical concerns.

4.4. Photothermal conversion mechanism

The photothermal heating effect represents a pivotal approach in the field of alternative therapeutic interventions, particularly in the context of cancer treatment. This phenomenon is primarily based on the photothermal conversion process, in which an incident optical energy is effectively converted into thermal energy [162]. This conversion occurs through several mechanisms, including plasmonic localized heating and non-radiative relaxation. As previously elucidated in Fig. 5d and e, plasmonic localized heating is predominantly observed in metallic nanostructures. Conversely, non-metals exhibit photothermal effects primarily through non-radiative relaxation (Fig. 5g). In this mechanism, following the absorption of incident light, the excited states in non-metallic materials return to their ground state via non-radiative emission (i.e., thermal relaxation). This process can be observed in various nanomaterials such as UCNPs, MoS₂, carbon-based materials, and some organic materials, which are known for their high thermal conductivity [32,[163], [164], [165]]. Given the larger absorption cross-sectional area, the ability of these materials to absorb light across various wavelengths and efficiently convert it into thermal energy renders them suitable candidates for photothermal therapy. Understanding these distinct mechanisms not only broadens the potential applications of photothermal therapy but also paves the way for the development of novel LRCs and strategies to enhance therapeutic efficacy against challenging diseases.

4.5. Photoacoustic conversion mechanism

The photoacoustic (PA) effect represents a sophisticated mechanism leveraged extensively in the field of preclinical and clinical biomedical diagnostics, particularly through the modern modalities of imaging and spectroscopy [166,167]. This phenomenon occurs when nanomaterials are subjected to pulsed or modulated light energy, leading to a series of energy transformations that result in acoustic signal generation (Fig. 5h). In essence, the PA conversion process begins with the excitation of nanomaterials by incident light, which, depending on the material properties, can result in localized heating due to the absorption of energy. This heating prompts thermal expansion within the material, which subsequently induces the generation of acoustic waves. These acoustic waves can be detected using ultrasound technology, providing a means to visualize or characterize the material's properties. Focusing on metal nanostructures, the PA effect is closely associated with LSPR (Section 4.3). When these nanostructures absorb light, the incident electromagnetic energy excites surface plasmon oscillations, which generate significant localized heating through electro-phonon coupling. This rapid thermal expansion due to LSPR is depicted in various studies, particularly illustrated in Fig. 5d and e, demonstrating the interactions between light and metallic nanostructures [168]. In contrast, for non-metallic nanomaterials, the absorption of incident light energy leads to the excitation of electrons. These excited electrons eventually transition back to their ground state via non-radiative processes (Fig. 5g), primarily involving energy release in the form of heat. This process manifests as thermal relaxation, where phonons, quantized sound or lattice vibrations, are emitted [26]. The heat generated during this electron transition again leads to thermal expansion, giving rise to acoustic waves similar to those produced in metallic counterparts. Overall, the integration of plasmonic behavior in metal nanostructures and the mechanisms of thermal relaxation in other nanomaterials amplifies the efficiency of the PA effect.

4.6. Photoelectric conversion mechanism

The photoelectric conversion effect, defined as the transformation of light energy into electrical energy, is a well-established phenomenon observed in intrinsically conducting or semiconducting polymers (e.g., P3HT) and nanomaterials (e.g., GO, MoS₂, g-C₃N₄). This mechanism finds significant application in tissue engineering, particularly in the manipulation of cellular behavior and the facilitation of neurogenesis [9,34]. In a fundamental process, incident photons are absorbed by the π-conjugated polymer chains or semiconducting nanomaterials, resulting in the creation of excitons, which are electron-hole pairs. Subsequently, these excitons undergo dissociation at the donor-acceptor heterojunctions (for instance, polymer/polymer and polymer/GO interfaces), generating free electrons and holes (Fig. 5i) [169,170]. The resulting free charge carriers are directed along continuous conduction pathways, ultimately reaching the terminal of the applied electric field in the surrounding electrolyte or across the cellular membrane. In investigations focused on photo-stimulated neurogenesis, various LRCs are employed, utilizing light to activate light-sensitive proteins or to trigger the release of neurotransmitters that modulate neuronal activity. Among polymer systems, P3HT-based heterojunction composites are particularly noted for their superior photoelectric conversion performance and have been extensively characterized as a suitable platform for neurogenesis research and other biological applications. For instance, in P3HT–PCBM or P3HT–nanocarbon systems (graphene, CNTs), the LUMO of P3HT (∼−3.0 eV) [171] is higher than the acceptor's LUMO (PCBM ∼ −4.0 eV [172] and CNTs ∼ −3.9 eV [173]), creating a built-in potential and subsequently driving charge carrier transfer across the interface (Fig. 5j).

5. Toxicity evaluations in the biological system

It has been noticed that the functional LRCs contain multiple material constituents, of which the understanding of their cellular and subcellular toxicity mechanisms (especially for inorganic materials) is imperative for the development of safe and effective therapeutic strategies. Cellular toxicity associated with these materials can occur through various mechanisms, primarily influenced by the physicochemical properties of the nanomaterials. For instance, upon exposure to light, certain nanomaterials (such as MoS₂) can activate photochemical reactions, leading to the generation of ROS. The uncontrolled and highly elevated levels of ROS can overwhelm normal cellular antioxidant defenses, resulting in undesired oxidative stress, DNA damage, and eventually cell apoptosis or necrosis of adjacent healthy cells. Furthermore, the interaction of inorganic materials with cellular membranes can also induce structural changes, compromising membrane integrity. This disruption can facilitate the release of intracellular contents and the influx of harmful substances, contributing to healthy cell death. Additionally, therapeutic agents may localize within mitochondria, disrupting the electron transport chain and ATP production, resulting in compromised energy metabolism and triggering apoptotic pathways.

In a pertinent study, Gu et al. [174] investigate the nanotoxicity of MoS₂. The research identifies the stable interaction of MoS₂ with potassium ion (K⁺) transport channels. Notably, the undesirable binding mode between the KcsA channel and MoS₂ highlights the potential for indirect damage to the delicate architecture of the selectivity filter, leading to significant leakage of K⁺ ions. This nonspecific binding is attributed to interactions governed by van der Waals forces, as well as the pronounced hydrophobic characteristics of MoS₂ nanomaterials. As for MXenes, the nanotoxicity is influenced by their size, surface chemistry, and the presence of surface functional groups [175]. It is well-known that carbon-based nanomaterials are one of the most prominently studied materials in the biomedical field. However, a relevant case study highlighted the genotoxicity of CNTs [176]. While several individual reports have reported DNA strand breaks when in contact with MWCNTs, the presence of too few in-vivo animal models makes it difficult to make general conclusions about their genotoxicity. Additionally, most metal nanoparticles exhibit remarkable biocompatibility; however, their pristine or unmodified nanostructures may result in relatively low bioavailability and undesirable clearance [177]. Given the potential concerns of using inorganic-based materials, it is rationally imperative to pay attention to systematic preparation and modification. The physicochemical modification of inorganic nanomaterials not only solves the toxicity issues but also controls their biodistribution and post-therapeutic clearance. In a relevant review article, Yang and colleagues have delineated the surface modification on the clearance of various inorganic nanomaterials [178]. From our perspectives, a substantial amount of future research efforts should focus on elucidating physicochemical modifications to design nanocomposites that maximize therapeutic efficacy while minimizing adverse effects.

6. Biomedical applications: preclinical and clinical insights

6.1. Molecular imaging

Bioimaging agents based on LRCs leverage external light stimuli to enhance contrast across various diagnostic modalities, particularly in optical techniques such as fluorescence, photothermal, and photoacoustic imaging. These processes primarily operate through well-established mechanisms involving photoluminescence, photothermal conversion, localized surface plasmon, and photoacoustic conversion, as explained in earlier Sections 4.3, 4.4, 4.5, 4.6. In the following discussion, we critically evaluate the design of LRCs, highlighting their advantages and impacts on various molecular imaging outcomes.

6.1.1. Fluorescence imaging (FLI)

An essential technique, such as FLI is used for visualizing biological processes occurring within cells and tissues. This method employs fluorescent markers that, upon exposure to specific wavelengths of light, emit optical energy that is subsequently detected by high-resolution cameras. In the specific context of LRCs, they either possess inherent fluorescent characteristics or are conjugated with fluorescence tags, which enhance their applicability in bioimaging studies. For example, the study conducted by Dai et al. [179] demonstrated the use of folate-conjugated gadolinium/PCM composites encapsulated with NIR absorbing dyes, specifically indocyanine green (ICG), for FLI of cancer cells. Similar methodologies have been employed by numerous research groups [18,[180], [181], [182], [183]], including Cheng and colleagues, who incorporated ICG dye within MOF-based hollow nanocomposites to facilitate FLI-guided therapy for cancer cells [180]. While ICG dye is a well-established fluorescence label, it is susceptible to issues such as photobleaching. To mitigate these limitations, a recent study by Dash et al. [184], employed IR-820 dye as a fluorescence label incorporated within graphene QDs-based nanocomposites. Although organic fluorescent dyes are widely utilized in in-vitro and in-vivo imaging, they often face challenges related to nonspecific tissue absorption and possess a limited fluorescent lifetime (typically <5 ns), which restricts their long-term imaging capabilities. In this context, LRCs that incorporate components with intrinsic fluorescence properties emerge as pivotal in advancing bioimaging technology. LRCs that comprise inorganic NPs and QDs are particularly advantageous due to their enhanced photostability, tunable optical absorption, and superior physicochemical stability [[185], [186], [187]]. A noteworthy investigation in this area was conducted by Dai's research group, wherein they developed NIR-responsive upconversion and semiconductor quantum dot-based nanocomposites designed to emit light in the second biological window (>1000 nm) [185]. This approach is beneficial as the reduced fluorescence emission at longer wavelengths minimizes background fluorescence and greatly enhances signal detection. As illustrated in their findings, UCNP-PDL1-based LRCs demonstrate significant targeting efficacy and imaging strength in tumor-bearing mice (Fig. 6a). Despite the promising results, it is essential to note that UCNPs are hindered by challenges such as high aggregation and low quantum yield (less than 1 %), which remain critical issues that warrant further investigation.

Fig. 6.

Molecular or bioimaging applications of various LRCs. (a) NIR-II two-plex fluorescence imaging of LRCs based on Er-doped upconversion nanoparticles and anti-PD-L1 proteins and PbS-aCD8 nanoparticle complex. Reproduced with permission from Ref. [185]. Copyright 2019 Springer Nature Ltd. (b) Time-dependent photothermal images of tumor-bearing mice exposed to folic acid-functionalized MXene-CuO-gambogic acid (FMCG)-based LRCs. Reproduced with permission from Ref. [190]. Copyright 2024 Wiley-VCH GmbH. (c) In vivo photoacoustic imaging of 4T1 tumor-bearing mice after treatment with different composite samples, such as Polymer-Au nanocomplex. Reproduced with permission from Ref. [132]. Copyright 2020 American Chemical Society.

6.1.2. Photothermal imaging (PTI)

Generally, PTI, which relies on a light-to-heat conversion mechanism (as illustrated in Fig. 5), is an advanced optical imaging technique that quantifies the thermal energy emitted by substances capable of absorbing incident light. A significant challenge in the field of biomedical imaging is the detection of non-fluorescent entities, such as metal NPs, particularly when their dimensions are considerably smaller than the optical wavelength. This size disparity results in very low scattering cross sections, complicating their identification. However, materials that can absorb light and subsequently convert this absorbed energy into heat can induce measurable changes in the refractive index of the surrounding medium. Materials such as metal NPs, MoS₂, Bi₂S₃, and MXenes, among others, are regarded as prime candidates for photothermal applications due to their high optical absorption and plasmonic properties. For instance, Liu et al. [188] reported the synthesis of MoS₂@PEI@IR820-based LRCs that achieved a remarkable PCE of up to 47 % under 808 nm laser irradiation. In the subsequent year, Dash and colleagues constructed much complex LRCs, such as Bi₂S₃@Fe/Mn-MOF, demonstrating even higher PCE values, reaching up to 54 % under similar irradiation conditions [189]. They attributed this elevated efficiency to the presence of Bi₂S₃ nanorods. In our understanding, Bi₂S₃ has a direct bandgap (∼1.3 eV) that, when combined with its anisotropic nanorod morphology and engineered defects, gives rise to an LSPR effect in the NIR region. This LSPR dramatically boosts the absorption cross section around 808 nm, allowing Bi₂S₃ nanorods to harvest NIR photons with high efficiency. Moreover, MXenes have emerged as promising PTI agents due to their inherent metallic conductivity, which facilitates efficient free-electron absorption across a broad spectrum. The delocalized d-electron bands of MXenes contribute to strong extinction in the first and second biological windows (700–1200 nm). Consequently, there have been numerous efforts to develop LRCs based on MXenes for photothermal imaging and various biomedical applications. In a recent design, Xiong et al. [190] Specifically fabricated NIR-responsive MXene nanocomposites for in-vivo PTI (Fig. 6b). Despite possessing robust photothermal characteristics, this particular MXene nanocomposite exhibited a PCE of only 29.4 %, thereby indicating substantial potential for further optimization and engineering.

6.1.3. Photoacoustic imaging (PAI)

The optoacoustic imaging or PAI, represents a cutting-edge biomedical imaging technique that adeptly merges the strengths of optical contrast with the high spatial resolution provided by ultrasonic methodologies (Section 4.5). This innovative approach effectively overcomes the limitations posed by restricted optical penetration depths in live biological specimens. The substantial body of preclinical research emphasizing PAI has elicited significant interest, showcasing its promising potential for a multitude of clinical applications as well as commercial viability. PAI enables the acquisition of detailed morphological, functional, and molecular data in studies involving both live animals and human subjects. Its capability to furnish intrinsic clinical indicators positions it as an invaluable asset for purposes ranging from early diagnosis to continuous treatment monitoring [191]. Various nanomaterials, including carbon-based structures, MXenes, and AuNPs, have demonstrated suitability for PAI, attributed to their superior optical absorption characteristics, particularly within the NIR spectrum [192]. In a notable research investigation, Sun and co-workers advanced the field by developing Ce6-modified carbon dots as a PAI contrast agent, effectively visualizing tumor tissues during therapeutic interventions [17]. Similarly, Zhao et al. [16] employed vanadium-based MXenes-BSA nanocomposites to conduct PAI of tumor sites, revealing critical information regarding intertumoral blood flow and oxygen saturation, which further informed treatment strategies. The efficacy of PAI is intrinsically linked to the optical absorption and scattering cross-section properties of the utilized nanomaterials. Due to their high electron density, pronounced LSPR effects, and enhanced photothermal conversion capabilities, these materials are often favored as PAI contrast agents. A significant contribution to this field was made by Luo et al. [132], who designed a polymer-gold nanocomplex aimed at monitoring tumor biometallization (i.e., the accumulation of metal ions or NPs within or on tumor cells and tissues) (Fig. 6c). From our viewpoints, the emergence of PAI, supported by the integration of advanced nanomaterials, underscores its transformative potential in clinical practice. As research progresses, the refinement of PAI technologies offers promising avenues for improved diagnostic capabilities and therapeutic monitoring, thereby solidifying its role as an essential modality in contemporary biomedical imaging.

6.2. Photo-active therapies

Photoactive therapies, which encompass modalities such as photodynamic therapy and photothermal therapy, employ optically-active material agents that selectively target and eradicate diseased tissues upon light and heat activation. These therapeutic approaches are increasingly recognized for their utility in treating a range of conditions, including various forms of cancer and bacterial infections. The advantages of photoactive therapies are manifold, including reduced systemic toxicity, high adaptability for diverse patient demographics, the potential to overcome multidrug resistance, precision targeting of affected cells, and the capability for combination with other therapeutic strategies. Subsequent sections will delineate the foundational definitions of various photoactive therapeutic modalities and assess their effectiveness in managing specific disease states.

6.2.1. Photodynamic therapy (PDT)

The PDT represents a minimally invasive therapeutic approach characterized by a two-step treatment process that incorporates three critical components: a photosensitizer (PS), visible or NIR light, and either molecular oxygen or hydrogen peroxide. Upon systemic administration, the PS preferentially accumulates in pathological tissues, maintaining a non-toxic state until activated by light exposure. The illumination instigates a photochemical reaction (as detailed in Section 4.2), wherein the PS transfers energy to surrounding oxygen molecules, resulting in the generation of ROS. These ROS inflict irreversible damage on cellular structures, ultimately leading to tumor cell apoptosis. Despite the inherent selectivity and low systemic toxicity associated with PDT, several challenges persist. These include restricted light penetration through biological tissues, diminished ROS production attributable to tumor hypoxia, and the poor aqueous solubility of various PS compounds. To mitigate these limitations, the development of light-responsive materials has been pursued. Such materials are engineered to enhance the controlled delivery of photosensitizers, improve tissue penetration, and amplify ROS generation. Sun et al. [193], demonstrated the potential of g-C₃N₄/gelatin-based LRC scaffolds loaded with FDA-approved chlorin e6 (Ce6) PS for PDT. This study revealed significant cytocompatibility alongside a remarkable enhancement in ROS generation, yielding a 95 % inactivation rate of breast cancer cells. In another investigation, Cao et al. [39] explored the efficacy of PDT using chitosan-functionalized MoS₂ nanocomposites loaded with Ce6. While conventional PS is effective in ROS generation, it necessitates an oxygen-rich environment, which is often compromised in hypoxic tumor microenvironments, limiting the therapeutic efficacy of PDT. Addressing the issue of hypoxia-induced resistance to PDT, a novel oxygen self-sufficient PS LRCs was developed by Chao's group, specifically the Ru-g-C₃N₄ system (Fig. 7a and b) [194]. According to their proposed mechanism, following uptake by hypoxic tumor cells and subsequent exposure to visible light, the nanosheets catalyze the decomposition of H₂O₂ and H₂O to generate O₂, while concurrently catalyzing H₂O₂ and O₂ to produce multiple ROS molecules (•OH, •O₂⁻, and ¹O₂) (Fig. 7b). Further, traditional PDT agents, which require UV–Visible light for excitation, face limitations related to light penetration and the ability to target deep-seated tumors. To address issues of target specificity and light transmission to deeper tissues, Park and colleagues reported the development of a cancer cell-targeted PS involving photoprotein-conjugated NIR-absorbing UCNPs [195]. Their design integrated core-shell UCNPs with low internal energy back transfer conjugated to recombinant proteins containing a PS (KillerRed; KR) and a cancer cell-targeted lead peptide (LP). Under NIR irradiation, the UCNP-KR-LP system generated superoxide anion radicals as ROS via NIR-to-green light conversion and demonstrated excellent specificity for targeting cancer cells through receptor-mediated cell adhesion (Fig. 7c). In preclinical xenograft models, this approach illustrated effective therapeutic outcomes in deep-seated tumors, particularly within groups containing the LP (Fig. 7d). We anticipate that the integration of advanced and smart materials within next-generation PDT platforms will facilitate the achievement of deeper treatment penetrations, provide precise spatiotemporal control over PS activation, and enable synergistic multimodal therapeutic strategies. This evolution in PDT technology holds significant promise for the advancement of more effective and personalized cancer treatment modalities.

Fig. 7.

Photoactive therapy applications of various LRCs. (a) Illustration of Ru-g-C₃N₄ LRCs: an oxygen self-sufficient photosensitizer with activated multiple ROS (•OH, •O₂⁻, and ¹O₂) for the efficient PDT of hypoxic tumors. (b) Proposed photocatalyzed ¹O₂ formation mechanism in hypoxic H₂O or H₂O₂ tumor microenvironment. Reproduced with permission from Ref. [194]. Copyright 2021 Elsevier B.V. (c) Schematic illustrations of cancer cell-targeted PDT using UCNP-KR-LP (top) and an efficient photon energy transfer pathway from UCNPs to KR (bottom). (d) Tumor volume after 9 (left) and 21 (right) days of treatment with different formulations. Reproduced with permission from Ref. [195]. Copyright 2023 Springer Nature Ltd. (e) Dynamic photothermal characteristics of polymer composite-based PTT agent. Top: Photothermal heating curve of PPAPA polymer nanocomposites under 1064 nm laser irradiation. Bottom: Linear correlation between cooling times and the negative natural logarithm of driving force temperatures to calculate photothermal conversion efficiency. Reproduced with permission from Ref. [201]. Copyright 2025 Elsevier B.V. (f) Schematic illustration of FA@MXene/CuO₂/GA nanocomposite: synthesis and underlying therapeutic mechanism. Reproduced with permission from Ref. [190]. Copyright 2024 Wiley-VCH GmbH.

6.2.2. Photothermal therapy (PTT)

It has been well documented that PTT is an innovative therapeutic approach that utilizes light energy to induce thermal effects within targeted tissues, commonly for the treatment of various types of cancer. This modality relies on the selective absorption of light by photothermal agents, which convert absorbed energy into heat, resulting in localized hyperthermia. For instance, this thermal increase can induce tumor cell death through mechanisms such as protein denaturation, disruption of cellular structures, and induction of apoptosis. The efficacy of PTT can be significantly enhanced by the use of light-responsive materials, which serve as photothermal agents. These materials are engineered to exhibit high PCE, ensuring that a substantial amount of the incident light energy is converted to heat. Various composites based on metal nanostructures [132,196,197], carbon nanomaterials [22,24,182,184,187,198], and 2D nanocrystals [16,38,58,60,190,199,200], among others, have been extensively exploited for this purpose. Recent advancements in nanocomposite platforms, such as MXenes-Mn²⁺-ovalbumin developed by Liu and colleagues, have reported promising PTT outcomes, demonstrating a maximum photothermal PCE of approximately 28 % [58]. Moreover, Chung's research group has made significant strides with their development of g-C₃N₄/CuMoO₄-based LRCs for treating hepatocellular carcinoma, achieving a maximum PCE of 56.7 % [199]. Furthermore, this nanocomposite exhibited a cancer-killing potency of at least 77 % in in vitro studies. In a competitive landscape for designing high-efficacy therapeutic platforms, Yang's group has made significant contributions with vanadium-based MXene/atovaquone@BSA (VAB)-reliant LRCs that exhibit remarkable photothermal capacity, with PCE values reaching 61 % [16]. In vivo studies demonstrated that the stable and potent photothermal effect of VAB under NIR irradiation (808 nm) not only facilitated the necrosis of tumor cells but also enhanced its peroxidase-like activity, resulting in significant tumor reduction. Despite the advantages of inorganic nanomaterials in PTT due to their superior optical and physicochemical properties, concerns regarding their slow biological excretion and retention in major organs of the reticuloendothelial system, particularly the liver and spleen, raise issues related to long-term toxicity, which limits their clinical applicability. To address this challenge, Cui and colleagues developed a polymer conjugate-based nanoparticle platform (poly-phenanthrol-phenazine, PPAPA), which exhibited high-temperature production with a PCE of 75.2 % under 1064 nm laser irradiation, comparable to the benchmark organic photothermal agent, SWCNTs (Fig. 7e) [201]. Following treatment with PPAPA, there was a marked reduction in relative tumor volume reported. However, the hydrophobic characteristics of PPAPA and its limited aqueous solubility may adversely affect therapeutic outcomes. Furthermore, prolonged laser exposure can cause photobleaching or structural degradation of the phenazine core in organic agents, reducing their heat-generating capacity over multiple treatment cycles. Nevertheless, ensuring long-term photostability often requires synthetic modifications or the addition of protective matrices, complicating formulation. Thus, a straightforward yet effective design for PTT agents is warranted for real-life anti-cancer treatment.

Another critical challenge in PTT is tumor resistance, frequently mediated by heat-shock proteins (e.g., HSP-70/90) [202]. Elevated temperatures may also result in localized tissue damage [203], underscoring the need for mild PTT strategies that incorporate heat-shock protein inhibition and targeted mechanisms. Xiong and colleagues have strategically designed a PTT agent utilizing folic acid-functionalized MXene/CuO₂/gambogic acid (GA) (Fig. 7f) [190]. Under the irradiation of an 808 nm laser, the nanocomposite effectively enhances the mild PTT (maximum temperature ∼50 °C) effect by suppressing HSP90 expression through the release of GA due to the excellent photothermal performance of Ti₃C₂ MXene nanosheets. Moreover, the biocompatibility and tumor-targeting capabilities of the FA-PEG-SH system further enrich this approach. We believe that future advancements in the design of PTT materials should prioritize improvements in biocompatibility and the minimization of potential side effects, thereby optimizing the therapeutic window of PTT. Overall, the integration of light-responsive materials in PTT presents a promising strategy for enhancing treatment outcomes, allowing for more precise and effective thermal ablation of tumor tissues. From a clinical standpoint, recent research in PTT has primarily concentrated on creating new agents that exhibit high PCE. Equally important are the precise regulation of local tissue temperature, the achievement of uniform heat distribution, and the reduction of non-uniform irradiation. These factors are essential for minimizing off-target effects and improving the precision of the therapy.

6.3. Controlled and triggered drug release

The LRCs serve not only as intrinsic therapeutic platforms but also as highly effective stimuli-responsive nanocomposite carriers aimed at alleviating various disease states. The key advantages of light-triggered release include spatiotemporal precision, on-demand dosage control, reduced systemic exposure, and non-invasive and patient-friendly. Various strategies have been developed to facilitate the controlled release of drug payloads, predominantly leveraging light-responsive mechanisms (Section 4). For example, the incorporation of chromophores or light-sensitive molecular components within LRCs enables structural transformations upon exposure to specific wavelengths of light, resulting in the triggered release of encapsulated therapeutic agents. Furthermore, the photothermal effect is attributed to LRCs that absorb energy from light at designated wavelengths, converting this photon energy into localized thermal energy. This thermal effect can enhance the diffusion rate of the payload from the nanocarrier or induce a response from thermosensitive nanocarriers, thereby facilitating the release of the encapsulated substances. Many advanced systems of light-triggered drug release incorporate a combination of these mechanisms, enabling a coordinated and systematic approach to drug delivery. This multifaceted release strategy is particularly advantageous in addressing complex biomedical challenges, including cancer and inflammatory diseases.

6.3.1. Light-triggered payload release for cancer treatment

Light, akin to other stimuli such as pH and glutathione, has emerged as a promising external control mechanism for the release properties of therapeutic agents. Recent work by Li et al. [204] introduced a proof-of-concept therapeutic platform utilizing rGO and polyethylenimine-dithiocarbonate (PEI-DTC) for the light-triggered release of hydrogen sulfide (H₂S) within cellular environments. Mechanistically, upon irradiation with 780 nm light, the rGO nanosheets within the nanocomposite generate thermal energy, which subsequently activates PEI-DTC to produce and deliver H₂S at a predetermined target site (Fig. 8a). Such platforms are deemed essential for achieving synchronous photothermal and gas-stimulation therapies. In a separate investigation, Juan Ge and colleagues proposed a therapeutic nanoplatform designed for the simultaneous activation of carbon monoxide (CO) and ROS release via an upconverted light transducer [205]. This system incorporates a photochemical oxygen releaser molecule (photoCORM, designated as 3HBQ) and a PS (Ce6) in conjunction with UCNPs. The lanthanide-doped UCNPs function as upconverted light transducers by absorbing NIR photons at 808 nm and converting them into blue and red photons. This dual photon emission triggers the release of CO from 3HBQ and activates Ce6 to generate ROS, thereby facilitating a combined approach of PDT and gas therapy (Fig. 8b). Furthermore, Shen's group proposed an innovative methodology utilizing thermo-responsive mesoporous silica NPs as a vehicle for the chemotherapeutic agent doxorubicin [206]. The incorporation of CuS NPs, which possess PTT capabilities, was aimed at achieving a synergistic effect between PTT and chemotherapy while ensuring controlled drug release (Fig. 8c). Under exposure to NIR laser irradiation, CuS NPs induce photothermal conversion, resulting in a temperature increase that triggers a phase transition of the polymer coating surrounding the NPs from a hydrophobic to a hydrophilic state. This temperature-induced response facilitates the precise release of doxorubicin from the mesoporous structures of the silica NPs (Fig. 8d).

Fig. 8.

Applications for various LRCs where light serves as an external trigger for the controlled release of a drug/gas molecule for cancer treatments. (a) Schematic illustration of the synthesis of a rGO–PEI-DTC nanocomposite and its light-triggered release of H₂S for suppression of cancer cell viability. Reproduced with permission from Ref. [204]. Copyright 2019 Royal Society of Chemistry. (b) NIR-light responsive nanocomposite based on UCNPs@Ce6/photoCORM 3HBQ@brain tumor cell membrane (UCNP@Ce6/3HBQ/CM) for ROS and carbon monoxide release to glioblastoma therapy. Reproduced with permission from Ref. [205]. Copyright 2023 Springer Nature Ltd. (c) Schematic diagram of CuS@MSN-PEG based nanocomposite for light-triggered drug release and combined cancer therapy. (d) Photothermal-triggered cumulative drug release. Reproduced with permission from Ref. [206]. Copyright 2024 Elsevier B.V. (e) Schematic representation of preparation and proposed mechanism of light-triggered self-delivery photothermal converter (CypCel) for cascading inflammation inhibition. Reproduced with permission from Ref. [209]. Copyright 2023 Elsevier B.V. (f) Overview of NIR-triggered H₂ generation from UCNPs-based nanocomposite for Alzheimer's disease therapy. Reproduced with permission from Ref. [212]. Copyright 2024 Elsevier B.V.

6.3.2. Light-triggered drug release for inflammatory disease treatment

Inflammation is a fundamental pathological process implicated in a diverse array of chronic diseases, including osteoarthritis [7] and periodontitis [130,207]. Notably, inflammatory side effects have also been recognized in certain PTT cancer treatments [208]. Conventional systemic administration of anti-inflammatory pharmacological agents frequently results in off-target effects, fluctuating drug concentrations, and challenges related to patient adherence. In contrast, stimuli-responsive drug delivery systems, particularly those utilizing light as a trigger, offer the potential for localized therapeutic effects, reduced dosing frequency, and minimized side effects, thereby enhancing both efficacy and safety. Recent research conducted by Zhao et al. [7] introduced a novel intra-articular drug delivery nanosystem, designated MoS₂@CS@Dex (MCD). This system comprises chitosan-modified MoS₂ nanosheets that serve as NIR photo-responsive carriers loaded with the anti-inflammatory agent dexamethasone (Dex). Their findings demonstrated that MCD exhibited responsiveness to NIR light both in-vitro and in-vivo, enabling the photothermal conversion-mediated release of Dex. This innovation facilitated remotely controlled release of Dex within the joint cavity by modulating the radiation properties of NIR light. MCD significantly prolonged the residence time of Dex within the joint, and its intra-articular administration in conjunction with NIR irradiation resulted in a marked enhancement of therapeutic efficacy at low systemic doses, effectively reducing cartilage erosion in osteoarthritis by inhibiting the secretion of inflammatory mediators such as TNF-α and IL-1β. In the context of periodontitis, an inflammatory disease driven by bacterial biofilms that leads to periodontal tissue destruction. Qi and co-workers developed an NIR-activated composite platform utilizing silica-coated AuNRs loaded with S-nitrosothiols (SNO) [207]. Upon thermal activation via the AuNRs, the SNO molecules are capable of releasing nitric oxide (NO) gas molecules directly at the site of periodontal inflammation, thereby exerting anti-inflammatory effects by attenuating the assembly of pro-inflammatory factors and inhibiting the NLRP3 inflammasome. Moreover, it has been observed that robust PTT employed for tumor ablation can also incite inflammatory responses that may inadvertently foster tumorigenesis, invasion, and metastasis. In response to this challenge, Zhou and co-workers developed a sophisticated nanocomposite platform designed for feedback-enhanced tumor therapy, which relies on hydrophobic and electrostatic interactions between the photothermal agent Cypate (Cyp) and the anti-inflammatory drug Celecoxib (Cel) (Fig. 8e) [209]. Under laser irradiation, the CypCel combination induces localized hyperthermia to inhibit tumor proliferation via Cyp-mediated PTT. Furthermore, the light-induced degradation of the CypCel complex facilitates rapid release of Celecoxib, contributing to the attenuation of the pro-inflammatory microenvironment instigated by PTT. Given the extensive implications of light-triggered drug release platforms in addressing critical therapeutic challenges, a thorough understanding of the underlying mechanisms of action and ongoing optimization of these systems is highly anticipated.

6.3.3. Light-triggered drug release for neurodegenerative treatment

In the context of neurodegenerative diseases, such as Alzheimer's disease (AD), targeted and controlled drug delivery is of paramount importance due to the intricate nature of these conditions and the necessity to minimize adverse side effects [210]. LRCs can be engineered to facilitate the release of therapeutic agents at designated sites within the brain, thereby enhancing therapeutic efficacy while mitigating systemic toxicity. In particular, the resident immune cells (i.e., microglia) of the central nervous system are integral to pathogen detection and elimination. Under resting conditions, microglia exhibit a ramified phenotype, enabling them to continuously monitor their microenvironment for molecular indicators of infection or neurodegenerative processes. Upon recognizing specific biomarkers, these immune cells undergo a reprogramming process to eliminate potential threats via phagocytosis process. However, with advancing age, microglia can undergo dystrophic changes, impairing their functional capabilities. To address this issue, Zhou and colleagues have developed a sophisticated optically active nanocomposite platform that enables the precise delivery of lipopolysaccharides (LPS) to re-activate microglia [211]. The UCNP@SiO₂ nanocomposite is meticulously functionalized with β-cyclodextrin through the specific affinity of this molecule for photo-responsive azobenzene and subsequently loaded with LPS. Upon exposure to NIR light, the trans-to-cis photoisomerization of the azobenzene moiety initiates the dissociation of β-cyclodextrin, leading to the release of LPS. This liberated LPS activates microglia via a toll-like receptor 4-mediated signaling pathway. Additionally, the infrared dye ICG, when excited by 800 nm light, generates localized heating, further promoting microglial activation through the upregulation of heat shock proteins. The ability to achieve controlled microglia activation through NIR-triggered drug release presents a novel therapeutic strategy for the in-situ treatment of various neurodegenerative disorders.

Zhang et al. [212] have recently developed an NIR-responsive upconversion nanoreactor composite platform for the delivery of hydrogen (H₂), which has demonstrated efficacy in mitigating tauopathy in the context of AD therapy (Fig. 8f). These nanoreactors are composed of biocompatible crosslinked vesicles that encapsulate ascorbic acid alongside two photosensitizers: chlorophyll and an indoline dye. Platinum NPs serve as photocatalysts, while UCNPs function as light-harvesting antennas within the nanoreacting system. Under NIR irradiation, these nanoreactors facilitate the in-situ release of H₂, which scavenges local excess ROS and attenuates tau hyperphosphorylation in an AD mouse model. It is crucial to acknowledge that the presence of the blood-brain barrier (BBB) and the intricate pathological mechanisms associated with AD can significantly hinder therapeutic efficacy. To address these challenges, Xiao's team has devised a multi-strategy nanocomposite system combining sialic acid-BSA-polydopamine (PDA) NPs with methylene blue/berberine NPs [213]. Under 808 nm NIR irradiation, PDA NPs enable NIR-triggered PTT by converting light energy into heat, thereby transiently opening the BBB and enhancing the delivery efficiency of the NPs. This process also facilitates the depolymerization of amyloid-beta (Aβ) fibrils. Furthermore, the catechol groups present on the surface of the PDA NPs can chelate excess metal ions in the brain, thereby reducing Aβ aggregation induced by metal ion interactions. While these innovative therapeutic strategies show considerable promise, the formulation of complex LRCs, which integrate drugs/PS/targeting moieties, demands adherence to stringent Good Manufacturing Practice regulations to ensure batch consistency. Overall, despite the unique approaches to BBB traversal and therapeutic payload delivery, several unclear issues persist in the literature. Specifically, the intricate nature of nanocomposite formulations raises pertinent questions regarding pharmacological stability, biodistribution, and clearance mechanisms. Importantly, these LRCs must successfully navigate the highly selective BBB without compromising their structural integrity or provoking inflammatory responses. Additionally, it must be noted that NIR light penetration is limited within brain tissue, and excessive or prolonged exposure poses the risk of generating heat and ROS, which can ultimately lead to damage to healthy neuronal cells.

6.4. Tissue engineering and regenerative medicine

The incorporation of LRCs, consisting of photoactive polymer conjugates combined with multidimensional inorganic nanomaterials, has emerged as a significant advancement in tissue engineering and regenerative medicine domains. These nanocomposites can be meticulously engineered to exhibit specific responses to targeted wavelengths of light, thereby enabling controlled drug release mechanisms, cell signaling pathways, and other biological processes associated with tissue regeneration. For example, the utilization of 2D-based LRCs is becoming increasingly prevalent in the fabrication of hydrogel or scaffolds designed to modulate cellular behavior for diverse applications in tissue engineering. The incorporation of inorganic materials into these systems enhances not only the mechanical properties but also provides photothermal effects that are conducive to wound healing. Such effects facilitate the promotion of cell proliferation, migration, and differentiation in response to light stimuli. Moreover, one of the notable applications of these LRCs lies in their capacity for photothermal and photochemical ablation of bacterial infections during wound healing processes. This highlights the multifunctional role of LRCs in both enhancing tissue regeneration and combating infections, underscoring their potential clinical utility.

6.4.1. Light-responsive smart materials for modulating cell behavior

Optoelectronic nanocomposites integrating semiconducting and photoactive materials have made considerable strides in the modulation of cellular actuation processes, including differentiation and regeneration. This advancement is predominantly facilitated by mechanisms such as photoinduced phase transitions and photoelectric conversion, which enhance the responsiveness of cellular systems to light stimuli. A recent investigation by Yuan and colleagues reported the development of a biocompatible fibrous membrane heterojunction comprising the photoactive polymer P3HT, PCL, and polypyrrole (PPY). This composite was shown to promote the neurogenesis of PC-12 cells upon photostimulation in vitro (Fig. 9a and b) [14]. While the in-vitro results indicated a promising capacity for neurogenesis, it is worth noting that the optical energy employed in the study was sourced from an LED with a wavelength of 532 nm, which may experience significant scattering and reduced penetration depth in in-vivo environments. Nonetheless, with further refinement of material properties and optimization of the incident light wavelength, such nanocomposites could be highly applicable for cellular patches aimed at optical and nerve regeneration. Additionally, research conducted by Zhang's group concentrated on neuron differentiation through the use of MoS₂/GO/polymer-based hydrogel LRCs [214]. The resultant hydrogel exhibited remarkable mechanical properties, electronic conductivity, and inflammation attenuation capabilities, consequently promoting the differentiation of neural stem cells while inhibiting astrocyte development. A crucial study by Saadati et al. [21] utilized scaffolds incorporating MoS₂ alongside other 2D materials to control the differentiation of human neural progenitor cells (hNPCs) through photostimulation (Fig. 9c and d). These scaffolds, constructed from rGO and MoS₂-MoO_3-x, demonstrated a significant enhancement in hNPC differentiation into neurons, with an increase by a factor of 4.4. The structural characteristics of the MoS₂-MoO_3-x nanostructures contributed to a substantially larger surface area conducive to cell adhesion, facilitating cell attachment, spreading, and formation of focal adhesions. Importantly, The study documented three primary observations: i) the nanosheet dimensions of MoS₂-MoO_3-x critically influenced their binding dynamics with proteins in the aqueous culture medium, enhancing interaction with the hNPC membrane, ii) the extensive surface area and nanoporous architecture promoted efficient protein adsorption, particularly in the formation of a protein corona, which plays a pivotal role in cellular adhesion and internalization, subsequently enhancing neural differentiation, iii) the superior electrical conductivity and strong LSPR properties of MoS₂-MoO_3-x positively influenced neural differentiation by facilitating charge transport at cellular membrane interfaces and regulating interactions at cell-cell or cell/biomaterial interfaces. Furthermore, the presence of numerous active edge sites (i.e., open metal edges) within the binary nanostructure of MoS₂-MoO_3-x facilitated the modulation of charge transfer through the heterojunction to hNPCs, thereby enhancing their differentiation potential. While the MoS₂-based platform exhibited significant capacity for cellular differentiation and adhesion, its clinical implications in real-life biological applications require further exploration, particularly concerning nanotoxicity issues. Additionally, the remarkable capability of CNT-based materials to facilitate the direct conversion of light energy into thermal energy, which is subsequently transformed into mechanical force through the photo-mechanical effect, has received significant attention in the field of materials science. To harness this phenomenon for applications in tissue engineering, Mosnáčková et al. [215] developed hybrid composites incorporating MWCNTs that are covalently bonded to poly(2-hydroxyethyl methacrylate)-grafted PCL (MWCNTs-PHEMA-g-PCL). These hybrid LRCs, consisting of 24 wt% MWCNTs, exhibit characteristics akin to thermoplastic elastomers, while maintaining elastic properties at temperatures exceeding 100 °C. Furthermore, the materials demonstrate exceptional, fully reversible, repeatable, and rapid photo-mechanical actuation behavior. This unique responsiveness positions them as promising candidates for manipulating various cellular processes, including migration, differentiation, and tissue assembly, which are pivotal for advancements in tissue engineering applications.

Fig. 9.

Applications for various smart LRCs for tissue engineering and regenerative medicines. (a) Immunofluorescent staining of neurofilament was used to assess neuronal differentiation of PC-12 cells on day 5 post-seeding on PCL, PCL/PPY, PCL-P3HT, and PCL-P3HT/PPY membranes, in the presence or absence of LED light stimulation (532 nm). (b) Corresponding quantitative integrated densities of neurons. Reproduced with permission from Ref. [14]. Copyright 2022 Elsevier B.V. (c) Ratio of neuronal cells and neuroglial cells to the number of nuclei when attached to different nanocomposite platforms, including rGO, MoS₂/MoO_3-x, rGO/MoS₂-MoO_3-x. (d) Schematic illustration of a neuron and different neuroglia cells. Reproduced with permission from Ref. [21]. Copyright 2023 American Chemical Society. (e) Time-dependent therapeutic outcomes followed by PTT-mediated bacterial killing of wound healing investigation on rats exposed to different MXene/MOF-based composite test samples. Reproduced with permission from Ref. [62]. Copyright 2023 Elsevier B.V. (f) Schematic illustration of photothermal and photocatalytic mechanism of ROS production in CuO@MoS₂ LRCs to utilize in in-vivo wound healing research. (g) therapeutic effects of nanocomposites and individual parts on MRSA-infected wounds in vivo. I: PBS (Control), II: Cu₂O, III: MoS₂, IV: Cu₂O@MoS₂, V: Cu₂O + NIR, VI: MoS₂ + NIR, VII: Cu₂O@MoS₂ + NIR. Reproduced with permission from Ref. [217]. Copyright 2024 American Chemical Society.

6.4.2. Light-responsive smart materials for promoting wound healing

Wound healing is a fundamental physiological process that aims to restore the integrity and functionality of the skin and other tissues following injury. However, this complex biological response is susceptible to disruption by various external factors, including bacterial infection and aggravated inflammation that can significantly hinder the healing trajectory and result in extensive tissue damage [216]. In response to these challenges, global researchers have been investigating a range of composite formulations aimed at enhancing wound healing outcomes. Among these formulations, smart LRCs have emerged as a particularly promising innovation within the field of wound healing. These advanced materials leverage the principles of photochemistry and photophysics to create interactive and multifunctional therapeutic strategies that actively contribute to the healing process. Importantly, these materials are designed with a focus on safety and biocompatibility, ensuring that they can be utilized effectively without adverse effects on the patient. One of the principal challenges in the field of wound healing, which is the provision of continuous and controllable oxygen around the injured tissue, while also addressing inflammation and facilitating the synergistic effects of oxygen supply and anti-inflammatory activities. To combat this issue, a groundbreaking study conducted by Li and colleagues in 2023 introduced a composite hydrogel system composed of PDA-hyaluronic acid (PDA-HA) hydrogel, which is loaded with calcium peroxide-ICG NPs, along with lauric acid and manganese dioxide (CaO₂-ICG@LA@MnO₂) [137]. The resultant LRCs demonstrated exceptional photothermal performance under NIR irradiation, enabling the controlled release of oxygen and ROS. This controllable and sustainable release of oxygen has been shown to promote the regeneration and repair of damaged tissue, while the generated ROS effectively mitigates the onset of inflammation during the early stages of wound healing.

Additionally, owing to their therapeutic nature, photocatalytic material-based composites are emerging as promising candidates for antibiotic wound disinfection. Recent work by Liu's group has focused on constructing MXenes/MOF-based composite formulations to augment photocatalytic performance through a face engineering strategy [62]. The Schottky junction formed at the interface of the individual components facilitates rapid electron transfer. Consequently, under NIR light irradiation, the efficiency of the photo-generated charge carriers results in the conversion of molecular oxygen to ROS and heat production, which disrupts bacterial cell membranes, significantly reducing the risk of wound infection (Fig. 9e). Given the pressing issue of drug-resistant bacterial infections, which pose a substantial threat to human health, a recent study by Li et al. [217] demonstrated the development of a simple nanocomposite formulation utilizing Cu₂O and MoS₂ for mild PTT-mediated wound healing applications (Fig. 9f). The intrinsic thermal properties of MoS₂, combined with the catalytic activities of Cu₂O, effectively eradicate multi-drug-resistant bacteria, restoring the wound to approximately 95 % of healthy tissue. Moreover, the advantage of mild PTT lies in its capacity to mitigate the damage to surrounding healthy cells, thus providing a safe and precise therapeutic approach for clinical applications (Fig. 9g). While inorganic nanomaterial-based composite platforms exhibit promising results, critical concerns regarding biocompatibility at the molecular level, structural stability, deeper tissue penetration, and uniform activation capacities must be adequately addressed. In our observations, current research efforts are concentrated on the exploration and refinement of the properties of these light-responsive materials to optimize their performance in clinical settings. By improving their efficacy and adaptability, these novel composites hold the potential to revolutionize the approach to wound care and significantly improve patient outcomes.

7. Challenges for clinical translations

The primary research findings highlight the significant potential of LRCs; however, several challenges must be addressed to facilitate their transition into clinical applications. The key limitations and considerations are outlined as follows.

• i)Biocompatibility: While biopolymer-based LRCs exhibit minimal toxicity towards biological targets, the potential adverse nanotoxicological effects associated with certain inorganic nanomaterials (e.g., ZnS QDs) necessitate thorough investigation and mitigation strategies.
• ii)Functionalization: Numerous strategies exist for the functionalization of these composites to fulfill diverse applications; however, the requirement for a precise selection of surface-active agents that do not compromise light responsiveness adds a layer of complexity to the development process.
• iii)Integration: Successful therapeutic outcomes often necessitate the combination of multiple components. However, the integration of different dimensional compounds with biological systems for drug delivery or imaging applications may present challenges in terms of compatibility and response kinetics.
• iv)Release mechanism: A comprehensive understanding of the mechanisms underlying stimuli-responsive controlled drug payload release is critical for designing functional and safe medicinal platforms. Our insights indicate that achieving precise control over the release of therapeutics in response to light requires further optimization of nanocomposite design.
• v)Light penetration: In-vivo clinical applications demand effective light penetration through biological tissues, which can be highly challenging for deeper structures. This necessitates the development of materials capable of responding to longer wavelengths of light. It is important to note that some drawbacks are associated with high-wavelength light. For instance, the NIR light permits deeper tissue penetration, but it also leads to reduced spatial resolution, with the diffraction limit increasing linearly with wavelength. Furthermore, optics optimized for infrared applications (including lenses, filters, and fibers) typically incur higher costs, require more bulk, and have stricter handling requirements. Additionally, the energy of photons decreases with increasing wavelength, thereby reducing the efficacy of photochemical reactions, such as those involved in PDT. Consequently, the optimization of the appropriate wavelength of light for targeted applications is of paramount importance.
• vi)Regulatory considerations: The regulatory landscape for light-responsive nanocomposite systems in biomedical applications is complex and multifaceted, requiring thorough evaluations across various dimensions. This encompasses toxicological assessments and the potential for adverse biological reactions upon implantation or exposure to biological environments. According to regulatory guidelines, it requires robust evidence of efficacy for its intended biomedical use. This includes following up on the preliminary investigations to confirm the findings discussed above and reproducing preclinical and clinical trials to establish that the light-responsive properties reliably achieve the desired therapeutic outcomes.
• vii)Manufacturing and quality control: Compliance with Good Manufacturing Practices (GMP) is essential to ensure consistent quality of the medicinal products. This includes standardized procedures and protocols for the synthesis, characterization, and scaling up of production.
• viii)Scale-up strategies: Successful scale-up strategies for light-responsive nanocomposite systems are essential and demand a multidisciplinary approach, integrating materials science, engineering, regulatory knowledge, and collaborative efforts to ensure effective translation from laboratory research to practical biomedical applications. Specifically, engaging with industrial partners, research institutions, and regulatory bodies can facilitate knowledge transfer, resource sharing, and innovation, thereby improving the overall development and scale-up process. Also, a critical initial step is the identification and reliable sourcing of high-quality raw materials.
• ix)Post-Market Surveillance: Ongoing monitoring of performance and safety post-approval is critical to ensure long-term reliability and identification of any unforeseen issues that may arise during clinical use.
• x)World cost assessments: In terms of material costs, the price of nanomaterials, which may include metals, semiconductors, or organic polymer compounds, is a critical consideration. In the current scenario, the overall market prices of these LRC systems are also subject to factors such as competition, intellectual property rights, and global economic conditions. Overall, the world cost assessments for LRCs in biomedical applications involve a multifaceted evaluation of material prices, manufacturing techniques, regulatory hurdles, and market dynamics, all of which significantly influence their commercial viability and accessibility in healthcare settings.

8. Conclusion and future directions

To conclude, the current review highlights notable advancements in LRC materials, specifically detailing their design principles, operating mechanisms, and innovative applications in the biomedical field. Given the comprehensive research undertaken on 2D, 1D, and 0D materials, their significance within the biomedical field is acknowledged on a global scale. As a take-home message, Table 1 summarizes the relationship between dimensionality and properties pertinent to biomedical utilization. Among the discussed multiscale composite materials, the biocompatible membranes and hydrogel systems are primarily composed of LRCs relying on 2D material (viz., GO/MoS₂) and 1D polymers (such as P3HT), which are often utilized in tissue engineering and regenerative medicine applications. Meanwhile, the other nano-dimensional pharmaco-active composite materials (nanosheets and NPs) are widely recruited for various therapeutic purposes in cancer and other disease fields. Particularly, in cancer treatment, the light source was explicitly used to modulate the drug release behavior externally, thereby providing control over therapeutic performance. Additionally, a part of the literature utilized the photo-catalytic 2D materials and 1D/0D plasmonic nanostructures in wound photo-stimulated cellular modulation and anti-bacterial directed wound healing applications. Nevertheless, the small-sized photoactive-0D material composites are used in various bioimaging applications. Looking ahead, there are several promising avenues for research and development in LRC materials. Apart from solving the potential challenges and limitations as described above, future studies could focus on enhancing the biocompatibility and biodegradability of these materials to increase their applicability in medical settings. Additionally, optimizing the specificity and efficacy of activation mechanisms, such as fine-tuning light wavelengths for targeted therapies, will be crucial. Moreover, interdisciplinary collaborations involving materials science, engineering, and life sciences could foster innovative solutions and novel applications. The integration of artificial intelligence and machine learning into the design process may also accelerate the development of tailored composites for specific biomedical applications.

Table 1.

LRCs: Dimensionality vs. key characteristics and preferred biomedical uses.

Multidimensional materials used in forming functional LRCs	Structural/Electronic origin	Key properties	Preferred biomedical use
0D (GQDs, SQDs, metal NPs)	Quantum confinement in all dimensions; Discrete energy levels	High surface-to-volume ratio; Tunable band gaps via size control; Strong LSPR function, particularly in metal NPs; Efficient NIR to thermal energy	Bioimaging; Light-triggered drug delivery system
1D (AuNRs, CNTs, Semiconductor polymer nanofiber)	Quantum confinement in 2D; Free transport along 1D	High aspect ratio; Highly anisotropic; Tunable LSPR functions in both NIR-I/II regions; Efficient photothermal characteristics; Enhanced imaging contrast attributed to elongated geometry; High electrical conductivity (e.g., for P3HT nanofibers);	Photoactive anti-cancer and anti-bacterial therapies; Stimuli-triggered drug release applications; Photostimulated cell behavior modulation applications
2D (GO, MoS2, MXenes, and Others)	Quantum confinement in 1D	Large lateral size and atomic thickness; Tunable bandgap, suitable for UV to NIR activation; Broad optical absorption characteristics; High thermal conductivity; High carrier mobility for photoelectric purposes	Light-triggered drug delivery system; Photoactive anti-cancer and anti-bacterial therapies; Tissue engineering and regenerative medicine

CRediT authorship contribution statement

Sandip Ghosh: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Chia-Jung Yang: Writing – review & editing, Visualization, Data curation. Jui-Yang Lai: Writing – review & editing, Supervision, Resources, Funding acquisition, Conceptualization.

Declaration of competing interest

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

Data availability

Data availability is not applicable to this article as no new data were created or analyzed in this study.