Recent advances of aggregation‐induced emission in body surface organs

The surface organs mainly comprise the superficial layers of various parts of the mammalian body, including the skin, eyes, and ears, which provide solid protection against various threats to the entire body. Damage to surface organs could lead to many serious diseases or even death. Currently, despite significant advancements in this field, there remain numerous enigmas that necessitate expeditious resolution, particularly pertaining to diagnostic and therapeutic objectives. The advancements in nanomedicine have provided a significant impetus for the development of novel approaches in the diagnosis, bioimaging, and therapy of superficial organs. The aggregation‐induced emission (AIE) phenomenon, initially observed by Prof. Ben Zhong Tang, stands out due to its contrasting behavior to the aggregation‐caused quenching effect. This discovery has significantly revolutionized the field of nanomedicine for surface organs owing to its remarkable advantages. In this review of literature, we aim to provide a comprehensive summary of recent advances of AIE lumenogen (AIEgen)‐based nanoplatforms in the fields of detection, diagnosis, imaging, and therapeutics of surface organ‐related diseases and discuss their prospects in the domain. It is hoped that this review will help attract researchers’ attention toward the utilization of this field for the exploration of a wider range of biomedical and clinical applications.

[4][5][6] Unfortunately, there is not yet a comprehensive understanding of the complexity of disease genesis and progression in surface organs, [7] which eventually leads to the failure of an effective therapeutic target.Generally, the occurrence of specific disease can be attributed to the collective impact of many factors, including genetics, hormones, and environmental factors.[13] To date, although many methods have been proposed and established to settle out the tackles of surface organ-associated diseases, [14][15][16][17] such as chemotherapy, stem cell therapy, and immunotherapy, the efficacy and therapeutic outcomes are still far from expectations.Therefore, it is still necessary and urgent to develop more effective diagnostic, bioimaging, and therapeutic approaches for body surface organ-associated diseases.
In recent decades, with the development of interdiscipline, many novel therapeutic strategies have been created and applied, which have made a large step toward better outcomes in all aspects of surface organ-associated diseases.28][29][30][31] Even though, there has been inspiring progress in terms of fundamental research as well as the clinical application of nanoparticles in this realm, a simple and novel strategy or an all-in-one kind of nanomaterial still needs to be developed.Currently, effective strategies are usually designed and constructed based on various conventional and rather complex components; however, limitations posed by the intrinsic properties of the conventional component have hampered any serious progress.An inevitable phenomenon known as aggregation-caused quenching (ACQ) of traditional fluores-cent probe leads to the substantial or even total quenching of the fluorescence (FL) intensity of targeted signal when in highly concentrated or aggregated form, and is accompanied by the potential to result in poor sensitivity, low stability, suboptimal efficacy, low signal-to-noise ratio (SNR), monofunction as well as severe toxic and negative side effects toward biological system.This, in turn, results in inaccurate diagnosis and detection outcomes and is wasteful in terms of high costs and bureaucratic procedures. [32]Although a few nanomaterial-based drugs, such as Abraxane, Feridex, and Resovist, [33][34][35][36] have also been approved for clinical application by the Food and Drug Administration, there is still much space for pursuing more effective nanodrugs for various diseases on account of growing demand.Fortunately, Prof. Ben Zhong Tang discovered a novel nanomaterial with an aggregation-induced emission (AIE) effect as opposed to the ACQ effect in 2001. [37]AIE effect is a photophysical effect, where the FL of an AIE luminogen (AIEgen) is activated by the formation of aggregates or solid power. [38]n the molecular mechanism, the AIE effect is attributed to the restriction of intramolecular motions (RIMs), including the restriction of intramolecular rotation in a molecule that exhibits no or very weak FL when suspended as an individual molecule.When placed in concentrated solutions or solid power, the restricted RIM thus prevents radiative decay, improves nonradiative decay, and enhances FL emission (Figure 1). [38,39]][42][43] Beyond the advantage of reversing the ACQ effect, AIEgens have many other advantages over traditional fluorophores, including alterable wavelengths ranging from the visible region to the NIR-II/III window (1000−1850 nm), large Stokes shifts, high quantum yield (QY), high photostability, high SNR, good biocompatibility and good safety, and so on. [44,45]For example, it has been shown that hexaphenylsilole, a typical AIEgen, is capable of achieving high resistance to photobleaching and high emission loss during stimulated emission depletion (STED) microscopy imaging, which further improves the level of spatial resolution and long-term imaging of STED, and broadens the scope of their applications in biomedical and materials science fields. [46]To date, many AIEgens with different properties have been synthesized chemically or discovered from natural sources, [47,48] and a specific online database, ASBase, has over 1000 entries of aggregate material systems with abundant information on AIEgen. [49][52][53][54][55] For instance, AIEgens have made great advances in the detection/diagnosis and treatment of various diseases, [56] including tumors, [57,58] as well as in neuroscience and the diagnosis, imaging, and treatment of neurological disorders, [40,[59][60][61] and so on.Presently, there is active research on the broader utilization of AIEgens in the field of biomedicine, particularly in relation to surface organ-associated disorders.Regrettably, a dearth of systematic and detailed synopses regarding the diverse biomedical applications of subject are still persisted.Given the prevailing situation, there exists a pressing requirement for a comprehensive synthesis of recent progress in the present state of research and development within this scientific domain.
For this purpose, this review literature aims to provide a comprehensive summary of the application of AIEgens in the field of diagnosis, bioimaging, and therapy of diseases affecting surface organs (Scheme 1).The initial summary and discussion is AIEgen-based nanomaterials utilized to detect and diagnose diseases affecting body surface organs.Then, AIEgen-based theranostics in surface organ-associated diseases have been summarized.Finally, the future perspectives regarding the application of AIEgens in this field have been discussed in detail.This review would contribute toward providing a deeper insight into the application of AIEgens in the diagnosis, bioimaging, and therapy of diseases and disorders affecting surface organs and would inspire more creative research aimed at improving the current state of body surface organ disease management in clinical contexts.

THE APPLICATION OF AIEgen-BASED NANOPLATFORM FOR THE DIAGNOSIS OF SURFACE ORGAN-ASSOCIATED DISEASE
[65][66] However, the light source is limited by the optical absorption and scattering resulting from various biological tissues, resulting in a bottleneck for FL imaging applications.[69][70] Simultaneously, fluorophores with AIE properties have manifested advantages in bioimaging with high QY, high photostability, and antiphotobleaching and/or quenching characteristics.For instance, an AIE probe named THPP was developed to visualize the blood vessels and deep internal organs simultaneously and dynamically by Zhang and colleagues. [71]TPA-Py, another probe, with an AIE unit has been applied to explore the changes in viscosity during the biogenesis and repair of acetaminophen (APAP)-induced liver injury. [72]In another work, Tang's group also received the first application of using AIEdots to identify ureters during surgery, providing a new platform for clinical in-surgery detection. [73]These findings indicate that the potential of AIEgens in the field of biological diagnosis is incredible.Therefore, this section presents an overview of the diagnostic advancements of AIEgens in disorders related to body surface organs.

The application of AIEgen-based nanoplatforms in diagnosing skin-associated disease
Skin diseases are the most common and typical human diseases around the world, occurring in all age groups, affecting 30%-70% of individuals, and in severe cases resulting in physical incapacity and even death. [74,75]Regrettably, there has been a lack of emphasis on skin diseases as a matter of worldwide public health concern.Therefore, the timely and accurate diagnosis of skin illnesses is of paramount importance, as it establishes a sound foundation for prompting intervention and mitigating the progression of the ailment.Nevertheless, the existing approaches for monitoring skin disorders exhibit several limitations, notably the absence of distinct biomarkers.Hence, the discovery of AIEgen has shed considerable light on this predicament owing to their significant benefits in terms of probes and imaging techniques, thereby aiding the advancement of FL-based diagnostic imaging approaches for various disorders (Table 1). [28,76,77]revious studies have revealed that skin damage occurs in around 95% of cancer patients who receive radiotherapy. [11]ytokine-based therapeutic strategies are the mainstream technique for treating skin damage caused by ionizing radiation; however, they are limited for application in instances of moderate radiation doses.Currently, stem cell therapy represents another promising approach for the treatment of radiation-induced injuries.Nevertheless, the precise function and ultimate fate of stem cells involved in the restoration of radiation-induced skin injury remain incompletely understood, mostly due to the absence of quantifiable cell tracking methods. [14,78]To apply stem cells for rescuing skin damage caused by radiation, Liu et al. utilized the properties of AIEgens of high NIR emitting organic nanodots to observe the fate and regeneration mechanism of adipose-derived stem cells (ADSCs) for the treatment of radiation-induced skin damage.They synthesized AIEgen (compound 4) with a typical donor-acceptor (D-A) structure, and then encapsulated it into nanoparticles by amphiphilic lipid-PEG 2000 -maleimide to generate AIE dots.The obtained AIE dots have a high QYs of 33% in aqueous solution, significant retention capacity in ADSCs, excellent biocompatibility during the period of ADSC differentiation and proliferation, and the ability to alleviate damage to radiation-induced endothelial cell injury.The results of in vivo studies demonstrated that AIE dots can serve as an efficient cell tracker to precisely track the cellular behavior of ADSCs after transplanted in mice with radiation-induced skin damage and contribute to understanding the therapeutic mechanisms of ADSCs. [79]This study provides a new perspective for the application of AIEgens in the radiation-damaged microenvironment.[82] However, because of the limitations posed by the size and heterogeneity of tissue of rejection sites, this method is not noninvasive and inevitably produces false negative results. [83]Therefore, it is an urgent need to develop more better noninvasive and sensitive diagnostic tools and methods for monitoring the immune response in recipients.To date, AIEgens have been developed as fluorescent probes for diagnostic testing of several diseases in this field. [84,85]Gao and colleagues developed a novel biomimetic dextran nanoparticle with AIE properties (GPs) for real-time noninvasive monitoring of the post-transplant immune response (Figure 2A).A series of positively charged NIR AIEgens named HBTTPEP were designed and synthesized in their study, which could aggregate and activate FL emission in GPs efficiently by a simple one-step incubation method (Figure 2B).By using a dectin-receptor, bionic HBTTPEP/GPs can selectively target macrophages, but not other immune cells, which move to the site of graft rejection.As a result, there was a substantial correlation between the FL detected by HBTTPEP/GPs and the level of allograft rejection and macrophage infiltration.The results of the in vivo experiment demonstrated a strong correlation between the degree of rejection and the fluorescent signal intensity of HBTTPEP/GPs in the transplanted skin.Additionally, macrophages acted as carriers, delivering HBTTPEP/GPs to the transplanted skin through lymphatic circulation (Figure 2C,D). [86]This work provides a prior prospective method for tracking macrophages in vitro and in vivo, allowing dynamic surveillance of the immune response of the recipient to the graft.

The application of AIEgen-based nanoplatforms in diagnosing ear-associated disease
The ear is one of the most important body surface organs in mammals to receive acoustic information.Due to its structure and physiology, the early diagnosis and treatment of ear diseases are beneficial in preventing further deterioration and progression of the disease.Hence, current techniques for imaging and diagnosis require significant improvement.Unfortunately, only a few studies have investigated the application of AIEgens in the treatment and diagnosis of ear diseases.To visualize the ear clearly, Yang and Hua developed a biocompatible AIEgen, named AQMN-3, for ear properties, this means that, following hydrophilic modification, AQMN-3 can be utilized as an NIR-II probe for in vivo imaging.After that, these three fluorophores were encapsulated into nanoparticles by the amphiphilic PLGA-mPEG, and AQMN-3 NPs with better luminescence properties were selected for mouse imaging experiments (Figure 3B).Under 690 nm laser excitation, different concentrations of AQMN-3 NPs exhibited strong NIR-II emission at both 900 and 1000 nm.Furthermore, distinct fluorescent emission at 1100 and 1200 nm were detected, confirming that AQMN-3 has great potential for bioimaging in biological systems.Once administered intravenously, AQMN-3 NPs can be employed in vivo to see mouse ear blood vessels and analyze their morphology at high resolution (Figure 3C). [88]This innovative development of emission dyes with AIE and NIR-II properties provides a novel strategy for the designation of organic materials for NIR-II imaging.However, more efforts are eagerly being made in the field of ear science.

The application of AIEgen-based nanoplatforms in latent fingerprints
The hand and finger are the most frequently utilized body parts and function as action executers.Individuals' fingerprints are a distinct trait that does not change throughout their lives. [89]Therefore, this conserved stable information has been coined as personal "ID cards" and "information banks", which have been adopted in criminal cases by collecting the information of latent fingerprints (LFPs) that arise when sweat-covered fingers touch an object.More important, the fingerprints have also been proved to be associated with specific disease potentially. [90]Therefore, it is crucial to develop an effective and precise technique for gathering LFPs for solving and preventing criminal cases and disease diagnoses.At present, traditional LFP modalities include the powder dusting method, chemical method, and fuming methods. [91]These methods, however, fail to provide abundant intact information on fingerprints.In the past years, some nanoparticle-based technologies have promoted progress in LFPs.These include quantum dots, [92] upconversion nanoparticles, [93] and carbon dots. [94]Again, these nanomaterials have not manifested the anticipated potential when applied to LFPs.
Due to the overwhelming advantages of AIEgen, they could be an excellent candidate for discovering and collecting the information of LPFs.For example, Zhu's group developed a novel AIEgen, named TPA-1OH, for gathering LPFs effectively and sensitively.First, TPA-1OH was synthesized by the nucleophilic addition reaction of 4-(diphenylamino)benzaldehyde and compound 1 (Figure 4A), TPA-1OH exhibited the maximum absorption peak at 458 nm in water solution (QYs: 0.058%), and the maximum emission was peaked at 660 nm with high QYs (7.5%).When exposed under 405 nm light, FL images of LFPs on rough surfaces, including walls, bricks, and paper, were observed without the necessity of soaking or spraying with organic cosolvents and post-treatment steps (Figure 4G).More importantly, it is biosafe at a concentration as high as 50 μM.When applied in an in situ model, real-time FL imaging was acquired easily, rapidly, and sensitively with clear ridges and high contrast (high contrast time: 11 s), wherein the exponential relationship between the relative FL intensity and time was deduced to be 0.48 s −1 (Figure 4C-E).Moreover, the level 1−3 details of LFP images dependent on TPA-1OH were received evidently and intactly, and level 3 details could be ridged and characterized by optical imaging and scanning electron microscope (SEM) with a sub-50 nm optical resolution (Figure 4H). [95]Apart from TPA-1OH, probes 1(a-c), [96] SAA/MMT, [97] Zn-BDI, [98] CFD, [99] TCMn, [100] and Zn(tpy-NMe 2 ) [101] have been developed and applied for LFPs, and suggest that AIEgens are better in comparison to conventional LFP probes.Moreover, the detailed decoding of disease with the application of AIEgen on latentprint is proposed to be an effective and easy after the association of both is identified.Therefore, there is great potential for developing better agent for LFPs in future.

AIEgen-BASED THERANOSTICS IN SURFACE ORGAN-ASSOCIATED DISEASE
As previously mentioned, disorders connected with the surface organs include burns, infections, and autogenous diseases (SLE, leukoderma, etc.).For disorders linked to surface organs, the diagnosis offers useful hints.However, more significant therapeutic interventions are required to treat or stop the disease's progression.To date, many nanomaterials have been developed for the treatment of surface organ-associated diseases in fundamental research, such as photocleavage nanodrugs [102] and 89 WP-MEL [103] for retinoblastoma, NP1 [104] and DSF-NPs [105] for glaucoma, MNFs@V-H@DA for wound healing, [106] KPV-Lipo for vitiligo, [107] and α-melittin-np for allergic dermatitis, [108] which bring great potential for the treatment of these diseases.Similar to the nanomaterials mentioned above and others, AIEgens also have great potential in the treatment of surface organ-associated diseases.In this section, we aim to provide a comprehensive review of AIEgen-based theranostics for surface organ-associated diseases (Table 2).

AIEgen-based theranostics in skin microorganism infection-associated wound healing
The inevitable external damage from physical and biological factors could damage the skin, especially caused by microorganism infection.126][127] Combined with the long-lasting FL imaging and the ability to track dynamic biological processes, [128][129][130] AIEgens have been prospects of application in the field of anti-infection.[137][138] More research should be focused on designing specific AIEgens for discriminatory imaging and killing of specified bacteria.The diagnosis and killing of bacteria could benefit the treatment of bacterial infections in skin wounds.Tang and coworkers, for example, created an AIEgen that can both stain and kill gram-positive (G + ) and gram-negative  5B).Furthermore, TriPE-NT's antibacterial effectiveness against both wild and clinically isolated MDR bacteria increased significantly with PDT, with a low degree of damage to mammalian cells (Figure 5C).This study evaluated the antimicrobial activity of TriPE-NT in vivo against bacteria infecting skin wounds in rats, and the results showed that the treatment with TriPE-NT formulation plus light irradiation inhibited S. aureus or S. aureus MDR-type bacteria to a higher extent than it inhibited Escherichia coli or E. coli MDR-type bacteria (Figure 5D).Thus, TriPE-NT can be used not only as a potent antibiotic for MDR bacterial infection diseases but also as a potential fluorophore to monitor bacterial infections. [109]eanwhile, Tang's team developed new AIEgens (TTPy) with sequentially enhanced D-A strength.Similar to TriPE-NT, TTPy can selectively kill G + bacteria, such as S. aureus in vitro via PDT, even in S. aureus-infected rat skin wounds. [110]The success of TTPy provides ideas for further MDR and antibiotic-sensitive bacteria. [111]This new AIEphage integration strategy provides valuable options for the development of antimicrobial drugs.
Based on the excellent PTT conversion efficiency of AIEgen, Ji and Wang synthesized a poly(dithieno[3,2b:2′,3′-d]pyrrole-benzo[1,2-c:4,5-c′]bis([1,2,5]thiadiazole)) (PDTPTBT) nanoplatform with AIE characteristics as a starting point for use as a photothermolysis agent against bacterial infections.The geometric and electronic properties of PDTPTBT were determined by density functional theory calculations.The polymer's conjugated backbone showed delocalization of the HOMO, while the LUMO was dominated by the central benzo[1,2-c:4,5-c′]bis([1,2,5]thiadiazole) (BBT) core.PDTPTBT's emission intensity progressively rose when it was suspended in the solution with increasing water content, indicating that it exhibited the usual AIE properties.To improve the dispersion of PDTPTBT in aqueous solution, PDTPTBT was encapsulated by liposomes to gain L-PDTPTBT.Under 808 nm laser irradiation, L-PDTPTBT exhibited a good bactericidal effect and could effectively eliminate gram-positive methicillinresistant S. aureus, Enterococcus faecalis, gram-negative E. coli, and Pseudomonas aeruginosa.The analytic results of the subcutaneous infection model suggested the bactericidal effect of L-PDTPTBT in vivo with a good synergistic effect of PTT.In addition, the use of L-PDTPTBT in combination with NIR for the treatment of a diabetic skin infection model also suggested its potential in treating superficial infections in immunodeficient individuals.Following NIR irradiation, L-PDTPTBT demonstrated faster wound healing than the control group, healed with an intact epidermal layer and even undamaged newborn hair follicles, and dramatically reduced the infection-related death rate in mice. [115]The combination of L-PDTPTBT with PTT provides newer prospects for the use of AIEgens in the therapeutic strategy against MDR.
The poor targeting of infected lesions and the incredibly low permeability of gram-negative bacteria to cell membranes (CMs) are the biggest treatment challenges for drug-resistant bacterial infections.To solve this issue, Prof. Tang and colleagues created a bionic neutrophil-like AIE nanorobot called CM@AIE NPs through nanoprecipitation with an amphiphilic copolymer (DSPE-PEG 2000 ) serving as a dopant matrix.The AIE NPs were coated with neutrophil CMs that were isolated from mouse bone marrow.To engage with immunomodulatory molecules for targeting, CM@AIE NPs could imitate source cells that benefit for the penetration in deep tissue.The PTT properties demonstrated under 980 nm laser irradiation enabled the CM@AIE NPs to show favorable antimicrobial effects in both in vitro and in vivo experiments, which helped to enhance the depth of the treatment, promote wound healing, and mitigate damage to skin tissue.Combined with the excellent PTT characteristics of AIEgens, this allows for precise targeting and treatment, minimizing damage to surrounding normal skin tissue.Furthermore, when used in conjunction with PTT treatment, CM@AIE NPs may enhance the expression levels of vascular endothelial growth factor (VEGF) and CD31, speeding up the process of vascular regeneration and wound healing. [116]The targeted antimicrobial performance of CM@AIE NPs reduces the risk of drug resistance, thereby providing a strategy for broadspectrum bacterial inhibition and opening up new prospects for clinical application.Also, other examples of the use of AIEgens for the treatment of skin wounds infected by bacteria have also been reported and summarized. [132]Zhu and Liu reported an AIE photosensitizer referred to as TCM-CPS, which has a low oxygen dependent, NIR-emitting, and fluorescent "switch".TCM-CPS kills bacteria to accelerate the process of wound healing under the inhibitory impact of PDT. [112]Zhong and Xie collectively prepared a novel hybrid hydrogel with AIE behavior by self-assembly with N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine (Fmoc-F) and berberine chloride (BBR), which was referred to as Fmoc-F/BBR.The Fmoc-F/BBR hydrogel showed effective antimicrobial activity against both E. coli and Staphyloccus aureu (S. aureus) via PDT.In addition, in vivo investigations on S. aureus-infected skin wounds showed that the Fmoc-F/BBR hydrogel promoted skin wound repair in rats. [113]Also, Tang and Dong developed an antimicrobial and biocompatible AIE nanofiber dressing using a handheld electrostatic spinning device for eliminating MDR bacterial infections and promoting the healing of bacterial-infected wounds. [139]Recently, novel AIEgens belonging to the class of 6-aza-2-thiothiothymine-modified gold nanocluster (ATT-AuNC) luminophores was constructed, it exhibited good antimicrobial activity against methicillin resistant Staphylococcus aureu (MRSA), and it also demonstrated the ability to modify the activity of multiple targets (Figures 6A and 7).ATT-AuNCs can generate abundant reactive oxygen species (ROS) efficiency to ablate MRSA through effective internalization into cells, therefore, ATT-AuNCs accelerate the healing process of skin wound infections (Figure 6B,C).These findings not only advance the current level of understanding but also open up new avenues for research into strategies to combat drug-resistant bacteria. [114]he above studies suggest that AIEgen is gradually being developed and prepared as a diagnostic and bacterial killing agent that can be used to specifically recognize bacteria in vivo and in vitro and effectively destroy them in the presence of PDT or PTT, thereby improving the treatment of skin wound infections.However, infection often accompanies with severe inflammation.Based on the therapeutic effects of PTT or PDT, the elimination of inflammation arises from infection usually utilizing the microorganism-killing strategy. [140]Therefore, more attention should be put into the field of synergistic therapy of anti-microorganism, antiinflammation and skin tissue regeneration, and its molecular mechanism.

AIEgen-based theranostics in skin burn wound healing
Burn is also an inevitable trauma caused by high or ultralow temperature, which usually induces excessive inflammation, tissue necrosis, and causes a series of serious alterations, the recovery of burn wounds involves anti-inflammation and skin regeneration, [141] therefore, an effective strategy is essential and urgent.In the past years, stem cells and generative exosomes have been regarded as the most promising modality for refractory wound treatment due to their capabilities of repairing damaged tissue, recruiting wound repair-related cells, and regulating immunity. [142,143]nder this circumstance, Liao et al. take advantage of exosome and AIEgens to construct a nanoplatform named THB@ANVs (adipose stem cells-derived nanovesicles, ANVs) for the cure of deep burn wounds (Figure 7A).endothelial cells.Then, a carboxymethyl chitosan and diactivated alkynemodified PEG (CMC-DA hydrogel) were loaded with THB@ANVs to constructe nanoplatform with low pH-responsive properties, which showed good biocompatibility and antibacterial effects.When applied in a deep burn wound model established by using burn equipment with parameters set at 500 g, 95 • C, and 15 s, and the hydrogels and S. aureus were dropped onto the wound surface to investigate the tissue repair promoting and anti-infectious ability, the results exhibited a smaller wound area of the ANVs or THB@ANVs hydrogel group on the day 7 and day 14 compared to control and hydrogen group, deeply.THB@ANVs hydrogel reduced the growth rate of bacteria, inflammation, promoted early angiogenesis and the deposition of collagen, suggesting the prevention of bacterial infections and promotion of wound regeneration of THB@ANVs (Figure 8E,F). [144]Therefore, the excellent therapeutic effect of AIEgen is an ideal agent for burn wound healing.

AIEgen-based theranostics in skin cancer
Malignant melanoma originates from melanocytes and represents the most perilous form of cutaneous malignancy.As a result of its pronounced tendency to undergo metastasis, melanoma exhibits heightened resistance to standard chemotherapy and radiation modalities.The properties of photosensitizers, such as efficient generation of 1 O 2 , selective and vast accumulation in cancer cells, as well as NIR excitation make them promising as PDT candidates.Zheng and colleagues proposed the molecular engineering of mitochondrion-targeted photosensitizers (PSs) by modulating D-A strength, resulting in an optimized NIR AIE photo-sensitizer (DCQu).The design of DCQu was initiated from CPy, with pyridine as the acceptor and carbazole fragments as the donor and π-bridge.The fluorescent carrier structure was further altered by substituting the pyridine component with a more potent electron-accepting quinolinium salt and/or incorporating an electron-donating diphenylamine at the carbazole terminus.This resulted in the production of DCPy with varying levels of CQu, DCPy, and DCQu (Figure 8A).DCQu exhibited high 1 O 2 generation efficiency, NIR emission (736 nm), high brightness, superior photostability, high specificity for mitochondria, and good biocompatibility.The DCQu was capable to identify cancer cells from normal cell and subsequently localizes to the mitochondria of these cells to irradiation using both single-or two-photon excitation.This process enhances the efficacy of PDT in eliminating cancer cells while minimizing damage to normal cells (Figure 8B,C).In addition, the results of selective ablation of melanoma cancer cells in vitro and in vivo exhibited the excellent antitumor effect of DCQu (Figure 8D,E). [117] I G U R E 9 (A) Diagram of PTT against B16F10 tumor based on NIR950@PMs@MN.(B) Diagram of preparing NIR950@PMs and NIR950@PMs@MN.(C) In vivo evaluation of PTT for melanoma tumors.Adapted with permission from Ref. [145].Copyright 2020, The Royal Society of Chemistry.
The success of DCQu will more effectively promote the molecular design of AIE-activated photosensitizer in biomedicine.
Most melanoma patients acquire drug resistance during treatment.AIEgen-based PTT exhibits great potential in the effective management of superficial cancers.However, AIEgen exhibits certain limitations with regard to its solubility and biodistribution.Under this circumstance, Wei and coworkers developed a system of dissolving microneedles (MNs) loaded with AIEgen (NIR950) for effective PTT treatment of melanoma (Figure 9A).First, NIR950-loaded polymeric micelles (NIR950@PMs) were prepared by nanoprecipitation to enhance drug dissolution.Subsequently, a two-step molding technique was employed to achieve the concentration of micelles on the tip of the MNs (referred to as NIR950@PMs@MN) (Figure 9B).It is worth noting that the emission intensity of NIR950@PMs did not exhibit a significant drop when subjected to continuous laser irradiation for 1 h.In addition, the utilization of pHresponsive micelles may facilitate the internalization process within cells by undergoing protonation in the acidic tumor microenvironments.Subsequently, NIR950@PMs were used by dissolving MNs for rapid accumulation at the tumor site and reaching the appropriate temperature for killing cancer cells effectively under laser irradiation.Interestingly, since the AIEgen-loaded micelles are concentrated directly at the tumor site, there is no drug wastage and no systemic distribution, reducing the occurrence of side effects.The findings demonstrate that melanoma tumors can be considerably ablated by NIR950@PMs@MN after just one low-dose administration and a single laser irradiation.Importantly, NIR950@PMs@MN enables high-resolution in vivo photoacoustic imaging due to the strong antiphotobleaching properties of NIR950 (Figure 9C).As a result, by monitoring the distribution of NIR950, laser irradiation can be accurately adjusted for complete excision of the tumor lesion.The introduction of NIR950@PMs@MN holds promise in the realm of PTT systems for melanoma treatment and paves the way for innovative research in superficial tumor therapy. [145]Beyond the PDT and PTT, we also have demonstrated that radiotherapy and immunotherapy were capable to kill the malignant melanoma effectively. [146,147]ased on the aforementioned findings, it is evident that AIEgen-based nanoplatforms have prospects of utilization in the field of skin cancer research and treatment.

AIEgen-based theranostics in fungal keratitis
Eyes have been claimed as the window of the heart, the lesion could cause not only physical pain but also mental stresses.There are a plenty of diseases discovered in the eye spot, such as infection, regression, cancer, and so on.For instance, fungal infections are a global health problem that cannot be neglected due to the continued emergence of antifungal resistance. [148,149]The significance and gravity of fungal infections in terms of their morbidity and mortality should not be underestimated, hence emphasizing the need for the development of efficacious antifungal treatments. [10]However, the molecular structure of the fungal receptor is altered by the fungus, thereby decreasing the affinity of antifungal drugs for the fungal receptor. [150,151]This phenomenon poses a great challenge for the development of safe and effective antifungal drugs. [152]To settle out this obstacle, Tang and colleagues investigated a mitochondria-specific PDT method based on the hydrophobicity of three cationic AIEgens (IQ-TPE-2O, IQ-Cm, and IQ-TPA) with isoquinoline (IQ) units for effective and selective fungal killing, to combat the infection caused by fungus in the eye (Figure 10A).Driving by the inherent surface charge potential difference between fungi and cells and extreme negative mitochondrial membrane potential, [118] the internalized AIEgens on the fungal surface were electrosensitive that benefit for the attachment to the fungal mitochondria, which further promotes the accumulation of cationic AIEgens in the fungus and facilitates the selective killing of a fungus with low side effects by IQ-TPE-2O, IQ-Cm, and IQ-TPA (Figure 10B).The results suggest that the mitochondria-specific PDT of AIEgens exerts antifungal activity based on an in situ 1 O 2 burst that disrupts the fungal mitochondria, followed by disruption of the CM under the influence of further irradiation, and it was responsible for fungal death (Figure 10C,D).Remarkably, in vivo tests have demonstrated that the administration of IQ-TPA using mitochondria-specific PDT significantly relieves fungal keratitis and the treatment is more effective than rose bengal utilized in clinical settings (Figure 10E).More importantly, this PDT technique requires only one injection of IQ-TPA during the duration of treatment, unlike clinical formulations of eye drops for fungal keratitis and other fungal infections.This will lessen the selection pressure on fungi. [118]And it provides the great potential and superiority of mitochondriaspecific PDT administration of IQTPA for the treatment of fungal keratitis.

3.2.2
AIEgen-based theranostics in bacterial keratitis Bacterial keratitis (BK) is an acute corneal infection and is one of the most leading causes of visual impairment and blindness worldwide. [153,154]Topical antibiotics are the conventional treatment for BK; however, there is a great risk of drug-resistant infections due to the abuse of antibiotics. [155]n addition to the destruction of corneal tissue, BK can result in consequences such as endophthalmitis, corneal leukoma, and corneal perforation that can even cause blindness if not treated promptly and effectively. [156,157]Therefore, it is urgent to explore a new, safe, and effective treatment strategy for BK.Similar to the diseases on the skin, it is reasonable for PTT and/or PDT to be applied in combating BK based on AIEgen due to the excellent therapeutic effect of antibacterial.To better treat BK and avoid antibiotic resistance, Prof. Tang's team developed IQ-Cm, a cationic diphenyl luminogen containing IQ and coumarin units with AIE, for the therapeutic investigation of BK (Figure 11A).IQ-Cm was synthesized via a simple synthesis method containing Suzuki coupling and a one-pot multicomponent reaction with a high yield (84%) (Figure 11B). [158]IQ-Cm is not significantly toxic to cells at certain concentrations and binds preferentially to bacteria.It was also found that IQ-Cm could act as a sensitive self-reporting probe to quickly differentiate between live and dead bacteria, and thus facilitate real-time self-monitoring of antimicrobial efficacy (Figure 11C).In addition, both the dark antimicrobial activity of IQ-Cm and its ability to efficiently generate ROS under PDT resulted in good bactericidal efficiency against S. aureus in vitro (Figure 11D).Moreover, a rabbit model of BK infected with S. aureus under PDT treatment showed significant antimicrobial activity after injection of IQ-Cm (Figure 11E).This study presents a novel treatment approach that demonstrates high sensitivity and efficacy in identifying different bacterial stages and implementing combination therapy.This approach is based on the inherent dark antibacterial activity of BK and the therapeutic effects of PDT. [159]ecently, Prof. Tang and coworkers synthesized another AIEgen named TTVP with good PDT effect, and it was applied in treating BK.TTVP was first synthesized via Suzuki−Miyaura coupling reaction of 4-bromo-N,Ndiphenylaniline with (5-formylthiophene-2-alkyl) boronic acid to form 5-(4-(diphenylamino)phenyl)thiophene-2carbonate aldehyde, and a condensation reaction with a pyridine salt subsequently was introduced to produce TTVP, which owned a typical D-A structure. [160]Similar to IQ-Cm mentioned above, TTVP has an extremely low toxicity and good biocompatibility even at high concentration.In addition, it selectively binds to S. aureus in the normal ocular environment.Upon light irradiation, TTVP exerted potent antimicrobial activity in vitro by generating efficient ROS.More significantly, the administration of TTVP could inhibit the degree of corneal turbidity, inflammatory infiltration and restricted the propagation of inflammation in a rat model of S. aureus infection.Notably, in cases of acute BK, the antibacterial activity of TTVP was outperformed than levofloxacin.These results demonstrated that the potential of TTVP as a PDT photosensitizer for BK in ocular infection clinics is limitless. [160]

FUTURE OUTLOOKS AND SUMMARY
Early and accurate detection of body surface organ diseases is necessary and vital to understand the onset and progression of disease pathology, and to provide early, targeted treatment, which not only relieves the patient's suffering but also reduces their financial burden.While there is no doubt regarding the significance of early detection, even greater focus should be placed on successful treatments and improved patient outcomes.[163][164][165][166][167] However, these biomaterials still have significant disadvantages that cannot be ignored, such as the complicated designation, potential biological hazard, and so on.From the point of view of biological applications, AIEgen has a lot of intrinsic advantageous properties compared to traditional nanomaterials, such as broad FL emission, high SNR, high photostability, high QYs, good biocompatibility, and so on, which makes AIEgen more attractive in bionanomedicine development and lays a solid foundation for further researches and applications. [168]In addition, AIEgens have already made great strides in the detection, imaging, diagnosis, and therapeutic aspects of many diseases.We hereby present the latest advances in the application of AIEgen-related technologies in the detection/bioimaging, diagnosis, and treatment of diseases affecting body surface organs, primarily the skin, ears, and eyes.The applications of AIEgens in body surface organ-related diseases have been summarized in this review, which additionally provides meaningful references for further improvement and development of AIEgens in biomedical research.
AIEgens emerged as a group of fluorescent nanomaterials useful for the diagnosis and imaging of several diseases.They exhibit intense emission during the formation of singlemolecular aggregates and can overcome the shortcomings imposed by the notorious ACQ effect, thereby significantly contributing to the development of bionanomedicines, [38] which guarantees the broad concentration range of interest.Furthermore, as described in this literature review, AIEgens have been shown to posses multifunctional effects and the much sought-after "all-in-one" property, suggesting their significance in synergistic therapies.][171][172][173] It also implies that while the use of AIEgen for various applications relevant to body surface organs faces great challenges, it also represents a promising opportunity.
Regarding the use of AIEgen-based nanomaterials in the investigation of diseases affecting the surface organs of the human body, a few crucial aspects necessitate attention.The examples provided in this review demonstrate the following items: (1) There is great potential for further expansion in the investigation and application of AIEgens in the context of various body surface organ diseases, including nasal disorders, dental disorders, and anal disorders.As per the available literature, there is currently no pertinent pub-lication documenting research on AIEgens in relation to these disorders.This is the direction in which AIEgens can further make great breakthroughs in body surface organ disease research; (2) Only a few studies have been conducted on the use of AIEgens for the treatment of body surface organ diseases.The "all-in-one" property of AIEgens is worth broader and deeper exploration in the realm of disease treatment.Hence, it is an important task to extend the research of AIEgens to other body surface organ diseases; (3) The microenvironment components, such as pH, viscosity, ROS, cytokine, and so on, responsive AIEgen nanoplatform should be developed to enhance the therapeutic outcomes further; (4) In the field of disease detection and diagnosis, it is generally encouraged to combine the two modalities as theranostics to obtain comprehensive physiological and pathological information about the patient, thus taking full advantage of AIEgens; (5) More efforts are needed to elucidate the potential of AIEgens for in vivo therapeutic use in models of body surface organ disease, other than small animals.It is imperative to validate these procedures in tissues or more intricate organs, such as large animals or human beings, to improve the clinical translation process.Nevertheless, the validation process in large animals or humans continues to provide significant difficulties and challenges.Further investigation into alternative sources of AIEgens should be undertaken to mitigate potential adverse effects associated with chemical synthesis.
Finally, although AIEgens currently show excellent biocompatibility, stability, and nontoxicity in both in vivo and ex vivo experiments, [174] studies on their total biological effects and interactions still need to be explored in detail. [175]herefore, a more comprehensive assessment of the effects of AIEgens upon the biological systems, which includes an investigation of the absorption and metabolism of these AIEgen-based nanomaterials, as well as the absence of significant toxic side effects, is required.Advanced therapeutic strategies are, therefore, a goal of both basic and clinical research and are likely to remain a research hotspot in the near future.Meanwhile, in order to better promote the application of AIEgen in the clinic, we think there are many works we must do to achieve better clinical application: (1) AIEgens have different physicochemical properties, which may exhibit different physiological responses than conventional nanomaterials after exposure to organisms.Therefore, it is necessary to establish a biological evaluation test system and declaration program suitable for the characteristics of AIEgen clearly; (2) The biosafety, including systemic toxicity, central neurotoxicity, reproductive toxicity, and immunotoxicity, is crucial for further biomedicine, which is urgent to be explored in short and long term, but also the clearance pathway in biological body; (3) Although there are AIEgen-based commercial kits for clinical diagnosis, we think the nearest way of AIEgen to clinical application is a biopsy in vitro, and although it is still long roadmap to develop therapeutic strategies in vivo, we have strong faith to achieve the goal in future.
In summary, this literature review focused on recent advances in AIEgen-based detection, diagnosis, bioimaging, and integrated treatment of body surface organ diseases.AIEgen has been dissected in detail and their shortcomings, future developments, and prospects for their clinical applications have been discussed in great detail.We hope this review could stimulate new ideas and directions for further exploration of AIEgens in body surface organ-associated diseases by developing more advanced AIEgens and facilitating their translation to clinical applications.It is anticipated that this review will provide new insights into the use of AIEgens in the full spectrum of body surface organ diseases and accelerate the pace of research and development in this area.The ultimate goal, of course, is to facilitate future detection, diagnosis, imaging, and treatment of body surface organ diseases.It is clear that AIEgens possess boundless potential for biomedical applications and hold a promising future in enhancing overall human health.

A C K N O W L E D G M E N T S
This work was supported by grants from the National Natural Science Foundation of China (82102904), the Science, Technology & Innovation Commission of Shenzhen Municipality (No. JCYJ20210324113405014), Hunan Provincial Science and Technology Plan Project (2021SK5001), and Joint project of Natural Science and Health Bureau of Hunan Province (2021JJ70136).The authors would like to thank all the reviewers who participated in the review and MJEditor (www.mjeditor.com)for its linguistic assistance during the preparation of this manuscript.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
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.

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I G U R E 1 (A) Molecular structures and photographs of a typical chemical molecule (perylene) possessing ACQ effect and (B) a chemical molecule (hexaphenylsilole, HPS) with AIE effect.(C) Diagram of the AIE molecular mechanism of the restriction of intramolecular motion (RIM).Adapted with permission from Ref. [62].Copyright 2020, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

S C H E M E 1
The schematic diagram of AIEgen-based nanoplatform for surface organs-associated diseases.

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I G U R E 2 (A) Diagram of HBTTPEP/GPs preparation and the tracking of macrophage-mediated HBTTPEP/GPs to the skin lesion.(B) Design principles of AIEgens.(C) Construction of the skin graft model and oral HBTTPEP/GPs to monitor allograft rejection.(D) Representative images of allogeneic graft rejection.Adapted with permission from Ref. [86].Copyright 2021, American Chemical Society.
vascular imaging with high resolution.First, a series of 2,20-(anthracene-9,10-diylidene) dimalono-nitrile (AQMN)based donor-acceptor-donor (D-A-D) type fluorophores with NIR-II emission and AIE properties were developed.Using triarylamine as the donor and strong electron acceptor AQMN as the core, three novel D-A-D-type AIEgens were created (Figure 3A).The lengthy alkyl chains aided in preventing tight accumulation and bursting of FL in aqueous solution, as demonstrated by the analytical results of the HOMO-LUMO energy gap and the deformed conformation of the compounds.Furthermore, the results of the FL emission demonstrated that AQMN-3 possessed an entire emission spectral range that could reach the NIR-II region when aggregated.Thus, AQMN-3 has superior FL emission F I G U R E 3 (A) Chemical structure of AQMN-1, AQMN-2, and AQMN-3.(B) Results of luminescence analysis and schematic diagram of preparation AQMN-3 NPs.(C) Bioimaging of blood vessels in the ears of mice using AQMN-3 NPs.Adapted with permission from Ref. [88].Copyright 2021, The Royal Society of Chemistry.

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I G U R E 4 TPA-1OH for LPFs.(A) Schematic route of TPA-1OH.(B) Mechanistic diagram of LFP development based on TPA-1OH.(C-F) Real-time fluorescence observed in in situ development of LFPs on tinfoil with TPA-1OH.(G) Whole LFPs on different substrates.(H) Micromorphology of LFPs.Adapted with permission from Ref. [95].Copyright 2020, American Chemical Society.(G − ) bacteria.They achieved this by joining the AIE unit TriPE (fluorescent portion) with NT (antimicrobial piece) to create triphenylethylene-naphthalimide triazole (TriPE-NT) (Figure 5A).While the NT unit provides TriPE-NT with antibacterial activity, the TriPE unit's intrinsic capacity to generate FL allows TriPE-NT to monitor drug−bacteria interactions (Figure

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I G U R E 5 (A) Synthetic routes for the development of TriPE-NT.(B) Bright-field and fluorescent images of bacteria.(C) Visualizing TriPE-NTinduced morphological changes of bacteria with TriPE-NT-based PDT.(a) FE-SEM images.(b) FEHR-TEM images.(c) Elemental mapping images.(D) In vivo evaluation of TriPE-NT in the treatment of bacteria-infected wounds in rats.Adapted with permission from Ref. [109].Copyright 2018, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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I G U R E 7 (A) Diagram of the construction and working mechanism of THB@ANVs hydrogel.(B) TEM images.(C) Photoluminescent spectra of THB.(D) Plots of the emission intensity of THB.(E) Representative images and summary of the wounds healing after different treatments.(F) Histological analysis of wound tissues.Adapted with permission from Ref. [144].Copyright 2023, SCUT, AIEI, and John Wiley & Sons Australia, Ltd.

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I G U R E 8 (A) Molecular structures of AIEgens (CPy, CQu, DCPy, and DCQu) and their photophysical properties.(B, C) Selective targeting capability evaluation of DCQu in cancer cells.(D) Fluorescent images of two-photon excited fluorescence (top row) and bright-field (bottom row) stained with DCQu.(E) DCQu had a significantly greater therapeutic efficacy in suppressing tumor growth compared to Ce6 in vivo.Adapted with permission from Ref. [117].Copyright 2020, The Royal Society of Chemistry.

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I G U R E 1 0 (A) Molecular structure and diagram of AIEgens for selective PDT against fungi based on mitochondria-specific targeting.(B) Colocalization imaging of C. albicans stained with IQ-TPE-2O, IQ-Cm, or IQ-TPA and MitoTracker Green.(C) Flow cytometric analytic results after treatment.(D) Fluorescence images of the mixed species of C. albicans and stained HCE cells and the cytotoxicity of IQ-TPA against HCE cells with different treatments.(E) Disease progression of fungal keratitis in rabbits following various treatments.Adapted with permission from Ref. [118].Copyright 2021, American Chemical Society.

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I G U R E 1 1 (A) Diagram of IQ-Cm applied in the process of rapid discrimination and the combined effective treatment of BK. (B) Synthetic route and molecular structure of IQ-Cm.(C) In vitro discriminative imaging.(D) In vitro antibacterial test.(E) In vivo antibacterial tests and histopathological analysis.Adapted with permission from Ref. [159].Copyright 2021, The Royal Society of Chemistry.
Reported AIEgens-based nanoplatform for the diagnosis of surface organs-associated disease.
TA B L E 1 Reported AIEgen-based theranostics in surface organs-associated disease.
TA B L E 2development of new AIE and PDT antimicrobial nanodrugs and guidance for clinical application.In another study, Tang's group designed and constructed another new strategy for specific antimicrobial targeting combined with FL monitoring, phage targeting, and AIE-based PDT inactivation.Briefly, AIEgens were combined with phages to form a new class of antimicrobial biocouplers (TVP-PAPs) for imaging and killing certain bacteria.TVP-PAP's distinct FL characteristics and targeting specificity have been allowed for successful applications in differential imaging, accurate targeting, and effective target bacterial killing without having a deleterious effect on normal cells.It is interesting to note that in vivo research has demonstrated a considerable acceleration of the healing process for skin wounds infected with