Applications of Aggregation-Induced Emission Materials in Immunology: From Diagnostics to Immunotherapy.

Introduction

AIE materials represent a unique class of compounds that display significantly enhanced optical emission in aggregated states. Unlike conventional fluorescent materials, AIE materials exhibit weak luminescence in solution but show a dramatic increase in the emission efficiency upon molecular aggregation. This phenomenon arises from the restriction of intramolecular motion caused by intermolecular interactions. These distinctive properties confer unique advantages to AIE materials, especially in biomedical applications such as disease diagnostics, immunofluorescence imaging, and immunotherapy, where they hold great promise for advancing medical technologies.

In recent years, research advancements have led to an expansion of AIE materials’ applications across diverse areas, including bioimaging, immunotherapy, and drug delivery. Notably, in the field of immunology, AIE materials have demonstrated remarkable progress in disease monitoring, fluorescence imaging, and immunotherapy. They can function as highly sensitive fluorescent probes for detecting immune molecules and biomarkers, while also serving as immunodrug platforms that enhance immune responses and therapeutic efficacies. Furthermore, their high stability, low photobleaching, and excellent biocompatibility make AIE materials particularly valuable for long-term fluorescence imaging and vaccine applications in disease management. ,

As the demand for improved disease diagnosis and immunotherapy grows in immunology, AIE materials have emerged as promising tools for both research and clinical applications. Meanwhile, challenges related to biocompatibility, immunotoxicity, and clinical translation remain obstacles to their broader implementation in the field. Addressing these issues requires further investigation and optimization.

This review focuses on recent advances in the application of AIE materials in immunoanalytical diagnosis, immunofluorescence imaging, and cancer immunotherapy, while discussing the challenges they face and potential directions for future development ( Figure ).

The Fundamental Properties of AIE Materials

AIE materials are a class of compounds that exhibit significantly enhanced optical emission in the aggregated state. Unlike conventional fluorescent materials, AIE materials typically emit weak fluorescence in solution but demonstrate markedly improved emission efficiency in the aggregated state due to intermolecular interactions that restrict intramolecular rotation. This characteristic stands in stark contrast to aggregation-caused quenching (ACQ) materials, which usually exhibit strong fluorescence in dilute solutions but suffer from significantly weakened or even completely quenched fluorescence in the aggregated state due to nonradiative decay processes such as intermolecular π-π stacking or energy transfer. This fluorescence quenching phenomenon severely limits the application of ACQ materials under high-concentration or solid-state conditions.

In contrast, the unique luminescence mechanism of AIE materials, rooted in the restriction of intramolecular rotation, enables them to maintain high fluorescence emission efficiency even under high-concentration or solid-state conditions, often exhibiting even stronger luminescence performance. This property not only allows AIE materials to effectively reduce background noise in bioimaging, thereby improving imaging resolution and sensitivity, but also endows them with excellent stability and low photobleaching, making them highly suitable for long-term imaging and real-time monitoring applications. These advantages have positioned AIE materials as powerful tools in the biomedical field. Further, experimental data have clearly demonstrated that the introduction of conjugated frameworks into the molecular design of AIE materials can effectively reduce the nonradiative energy loss caused by molecular vibration/rotation, resulting in a significant increase in fluorescence quantum yield. By carefully adopting the D-π-A or D-A-D structural configurations, we can precisely control the energy level distribution, which not only leads to a redshift in the emission wavelength and enhances the efficiency of ROS generation but also greatly improves the photostability of the materials. These thoughtfully designed strategies have achieved remarkable improvements in the field of synergistic tumor phototherapy, fully demonstrating their enormous potential for clinical translation and application.

For instance, in bioimaging, , AIE materials can display bright fluorescence signals in high-concentration regions within cells or tissues, such as cell membranes or organelles, thereby enhancing imaging contrast and resolution. In immune monitoring, AIE materials can be used to design highly sensitive fluorescent probes for real-time tracking of immune cell activities or detecting biomarkers. Additionally, in cancer treatment, AIE materials can not only serve as fluorescent markers for tumor localization but also enable precise tumor therapy through photodynamic therapy (PDT) or photothermal therapy (PTT). Therefore, while overcoming the limitations of ACQ materials, AIE materials provide novel research tools and therapeutic strategies for the biomedical field. ,

Recent studies have further concentrated on optimizing the molecular structures of AIE materials to enhance their optical properties and biocompatibility, thereby improving their performance in complex biological environments. Structural modifications, such as the introduction of specific functional groups or the modulation of molecular rigidity, have been demonstrated to significantly enhance the fluorescence quantum yield, photostability, and Stokes shift of AIE materials. These improvements enable their effective utilization in advanced applications such as high-resolution cell imaging, real-time biosensing, and targeted theranostics. For example, tailored AIE luminogens (AIEgens) have shown exceptional performance in tracking dynamic cellular processes and detecting biomarkers with high sensitivity and specificity, underscoring their potential in both fundamental research and clinical diagnostics.

In summary, the core mechanism of AIE materials, which relies on the restriction of intramolecular rotation, not only distinguishes them from ACQ materials but also underpins their superior optical properties and biomedical applicability. By leveraging their unique characteristics, AIE materials are paving the way for innovative solutions in bioimaging, disease monitoring, and therapeutic interventions.

Applications of AIE Materials in Immunology

AIE materials are rapidly expanding their applications in the field of immunology, particularly in cancer immunotherapy, immune cell tracking, and immune biomarker detection. In cancer immunotherapy, AIE materials can serve as novel photosensitizers, enhancing the immunogenicity of drugs and improving therapeutic outcomes. Additionally, these materials can be used to label immune cells, allowing researchers to monitor their dynamic behavior in vivo and gain deeper insight into immune responses. Furthermore, AIE materials have enabled high-sensitivity detection of immune biomarkers, enhancing the accuracy of early disease diagnosis and monitoring. Overall, with their excellent optical properties and good biocompatibility, AIE materials present new opportunities for immunological research and clinical applications.

Applications of AIE Materials in Disease Immune Diagnostics

Early diagnosis of diseases is critical for improving treatment outcomes. While traditional diagnostic methods such as biopsies and imaging techniques are widely used, their accuracy and sensitivity can be limited, especially in detecting tumors at microscale and early stages. , Consequently, the development of more sensitive and specific diagnostic tools has become a crucial challenge in disease management. In recent years, AIE materials have demonstrated tremendous potential in the field of disease immunodiagnostics due to their unique optical properties. They are particularly promising for real-time detection of cancer immune biomarkers, infectious disease viruses, and dynamic monitoring of immune responses. Table summarizes the names of these AIE photosensitizers along with their corresponding biomarkers.

AIE Materials in Immunoassay Diagnostics for Cancer Biomarkers

Cancer is one of the most serious threats to human health worldwide today. According to statistics from the World Health Organization (WHO), cancer is the second leading cause of death globally, following cardiovascular disease, and it causes nearly 10 million deaths each year. The importance of cancer biomarkers in early diagnosis is reflected in several aspects. They can be detected at an early stage of cancer, even before symptoms appear, thereby improving the accuracy of early detection, which is closely associated with higher treatment success rates and better prognoses. Biomarkers possess specificity and sensitivity, assisting physicians in distinguishing cancer from other benign diseases, thereby reducing the risk of misdiagnosis and missed diagnoses. Further, testing for biomarkers can evaluate tumor characteristics, facilitating the development of personalized treatment plans that enhance therapeutic efficacy while minimizing side effects. These biomarkers are not only used for early detection but also for monitoring cancer progression and treatment response, helping doctors determine treatment effectiveness and adjust plans as necessary. Additionally, biomarkers can be employed to screen high-risk populations, allowing for the early identification of potential cancer risks and enabling preventive measures to be taken. Research on these biomarkers also promotes a better understanding of cancer mechanisms and supports the development of new diagnostic tools and therapeutic strategies. Therefore, cancer biomarkers play a crucial role in improving the timeliness and accuracy of early detection, ultimately enhancing patient survival rates and the quality of life.

The high sensitivity and stability of AIE materials make them ideal tools for early cancer screening. AIE molecules, combined with biomacromolecules, can identify tumor-associated immune markers, while the tumor is still in its small or early stages, thereby providing strong support for early cancer detection.

Enzyme-linked immunosorbent assay (ELISA) is widely used for protein quantification due to its simplicity and low cost. However, the limited sensitivity and susceptibility of enzymes to environmental factors make it difficult to meet the demands of precise diagnostics, particularly in detecting low-concentration analytes. To address this issue, fluorescent-linked immunosorbent assay (FLISA) has emerged as a promising alternative, gaining increasing attention due to its higher sensitivity and signal stability.

The performance of FLISA is largely dependent on the choice of fluorescent labels. Although various fluorescent materials, such as organic dyes, quantum dots, and carbon nanotubes, have been used to enhance the detection sensitivity of FLISA, they still face several limitations, including poor photostability, aggregation-caused quenching (ACQ) effects, complex surface modification processes, potential cytotoxicity, and low quantum yields. In recent years, AIEgens have attracted significant interest due to their unique advantages. AIEgens not only exhibit high brightness, low background interference, and excellent photostability but also demonstrate good biocompatibility, making them ideal materials for constructing AIEgen-based sensors. However, the hydrophobicity of AIEgens and the need for specific conditions to activate their luminescence pose technical challenges for practical applications. Therefore, developing a method to directly generate fluorescent signals in AIEgen-based sensors has become a key focus of the current research.

AIE strategies often involve assembling AIE active molecules with targeting units (such as antibodies and peptides) into nanoparticles that serve as nanoscale probes to label targets. Li et al. designed a high-sensitivity fluorescence ELISA platform based on AIE materials ( Figure A). By embedding AIE materials in nanobeads, the platform significantly enhanced the stability and amplification of the fluorescent signal. In the study, AIE nanobeads were coupled with detection antibodies using carcinoembryonic antigen (CEA) as a model, demonstrating an ultrasensitive detection capability for protein biomarkers, with detection performance improved by 45 times compared to traditional methods. This approach offers immense potential for early diagnosis and clinical applications of diseases such as cancer ( Figure B).

Tang et al. expanded on prior work by developing a dual-mode ELISA platform based on AIE materials designed to efficiently detect cancer biomarkers such as prostate-specific antigen (PSA), which is associated with various types of cancer. In their design of the AIE-ELISA, they selected and employed the AIEgen tetraphenylethene-4A (TPE-4A). In the presence of hydrogen peroxide (H 2 O 2 ), horseradish peroxidase (HRP) catalyzes the oxidation of TPE-4A, transforming it into a substance with a significantly higher absorbance ( Figure A). After the reaction, deionized water is added, causing unreacted AIEgens to precipitate and emit fluorescence due to the restriction of intramolecular motion (RIM). When applied to the detection of PSA, a biomarker linked to prostate cancer, the AIE-ELISA demonstrated remarkable sensitivity, reducing the limit of detection (LOD) to 1.3 pg/mL, a significant improvement over single-mode ELISA. Additionally, the detection range was extended by 2 orders of magnitude ( Figure B), yielding dual signals of absorbance and fluorescence. By specifically recognizing cancer biomarkers, AIE materials enable precise diagnosis at early cancer stages, offering substantial support for treatment planning and showing significant potential in immunoassays, immunohistochemistry, and related fields. Furthermore, the high selectivity and low background noise of AIE materials provide strong anti-interference capabilities, thereby avoiding the misdiagnoses often caused by background interference in conventional fluorescent probes.

The combination of multiple biomarkers for analysis represents a more effective strategy than the use of a single biomarker, significantly improving the accuracy of early disease diagnosis. As a result, the development of multiplex analytical techniques capable of simultaneously detecting multiple targets has become a research focus. Among various point-of-care testing platforms, the lateral flow immunoassay (LFIA) has gained widespread application in clinical diagnostics, food safety, and environmental monitoring due to its rapid, convenient, and cost-effective characteristics. LFIA has shown great potential in multiplex detection, particularly in dual-modal LFIA systems equipped with multiple signal channels. These systems can simultaneously detect multiple biomarkers, enhancing sensitivity and detection range, while improving reliability and flexibility. Chen et al. developed a dual-modal LFIA platform based on fluorescent-colorimetric bifunctional nanoprobes (PFNPs), termed PFNPs-dLFIA, which demonstrated the capability of simultaneously quantifying inflammatory biomarkers, procalcitonin (PCT), and C-reactive protein (CRP). Three PFNPs with distinct optical properties (OAL-GPFNPs, OAH-OPFNPs, and OAL-YPFNPs) were used as label probes for the C, T1, and T2 bands, respectively. Through optimization of coupling conditions, such as pH and antibody labeling quantity, a sensitive dual-modal detection platform was constructed ( Figure C). Additionally, to achieve more accurate quantitative analysis, the study introduced an independent correction signal system based on IgY and antichicken IgG for ratio-based calibration in LFIA. This innovative multiplex LFIA technique not only provides a novel tool for efficient detection of inflammatory biomarkers but also demonstrates broad potential for clinical and diagnostic applications.

Magnetic nanoparticles (MNPs) play a significant role in immunoassays due to their rapid response to external magnetic fields and highly functionalizable surfaces. MNPs, when combined with an external magnetic field, enable the efficient separation and enrichment of target molecules, greatly improving detection sensitivity. Further, their surfaces can be functionalized with antibodies, nucleic acids, or fluorescent probes. When integrated with AIE materials, these systems provide enhanced detection capabilities. AIE materials, with their fluorescence-enhancing properties in aggregated states, form multimodal detection platforms with MNPs, achieving lower detection limits and improved signal reliability. This synergy shows great potential in biomarker detection, virus analysis, and point-of-care diagnostics, offering powerful tools for clinical diagnostics and precision medicine. Tang’s group developed an AIE-based nanoprobe for monitoring cancer immune biomarkers, specifically C-reactive protein (CRP) ( Figure A). Using EDC/NHS chemistry, they conjugated primary antibodies to AIE nanoparticles, while secondary antibodies were immobilized on magnetic nanoparticles. They synthesized three different nanoparticle sizes and used the Biotek H1mf 550/10 detection channel to demonstrate that the fluorescence signal of the AIE-PSCNPs correlated directly with antigen concentrations. AIE-200 nm-PSCNPs were chosen as a representative system for constructing Mag-AIE biosensors, enabling optimized detection behaviors. A noticeable decrease in particle size correlates with an increase in fluorescence intensity and a decrease in the limit of detection (LOD). Specifically, the LOD values for AIE-PSCNPs with diameters of 400 and 300 nm were determined to be 0.61 ng·mL –1 and 0.46 ng·mL –1 , respectively, with their associated standard curves illustrated ( Figure B and C). For the AIE-200 nm-PSCNP, the standard curve was established over a wide concentration range from 0.5 ng·mL –1 to 1000 ng·mL –1 ( Figure D and E). This approach combined fluorescence immunoassay (FIA) with magnetic separation to develop an ultrasensitive quantitative detection method, enabling rapid and efficient point-of-care diagnostics. Notably, the entire detection process was completed within 10 min, making it a fast and ideal tool for real-time monitoring of tumor immune biomarkers. This highlights the potential of AIE-based MNP systems for rapid and efficient cancer immunodiagnostics.

Ma et al. proposed a novel fluorescence immunoassay method combining silver nanoparticle (AgNP) amplification with AIE probes for highly sensitive detection of disease biomarkers ( Figure F). The method utilizes the dissolution of AgNPs to release a large number of Ag + ions, which interact with tetrazole acid-Ag + complexes to drive fluorescence emission from the Ag + -AIE probes. As a proof of concept, the assay demonstrated a linear detection range for alpha-fetoprotein (AFP) between 0.1 ng/mL and 5 μg/mL, with a limit of detection (LOD) as low as 42 pg/mL ( Figure G and H). This method successfully detected AFP in real serum samples from hepatocellular carcinoma (HCC) patients, highlighting its significant potential for clinical diagnostic applications.

Liu et al. synthesized a biotin-conjugated H4TCPE as an AIE-active molecule and assembled it onto the surface of mesoporous silica nanoparticles, resulting in biotin-enriched H4TCPE dendritic mesoporous silica nanoparticles (BDMSNs) ( Figure ). These BDMSNs were successfully integrated with multiplex lateral flow immunoassay (MLFIA) for the simultaneous detection of ovarian cancer biomarkers, including cancer antigen 125 (CA125) and human epididymis protein 4 (HE4). The biotin–streptavidin affinity interaction was employed to enhance the fluorescence signal, and secondary antibodies were labeled onto the BDMSNs to ensure efficient signal enrichment. The BDMSNs-MLFIA demonstrated detection limits of 5 U/mL for CA125 and 5 pM for HE4. Notably, this approach showed a high correlation with the commercial electrochemiluminescence detection method, with correlation coefficients exceeding 98%. BDMSNs-MLFIA represents a novel strategy for the simultaneous detection of CA125 and HE4 in clinical human serum, significantly improving the practicality of lateral flow immunoassays (LFIA) and emphasizing its potential in precision medicine.

AIE Materials for Immunoanalytical Diagnosis of Infectious Disease Viruses

The immunological detection of viruses holds significant importance in medicine and public health, enabling early diagnosis, effective prevention of viral transmission, and personalized therapeutic strategies. By identifying specific antigens or antibodies, immunoassays can accurately evaluate a patient’s infection status and guide precise treatment plans. Additionally, these techniques play a pivotal role in vaccine development and efficacy assessment by monitoring antibody levels, thus evaluating vaccine immunogenicity and protective effects while optimizing vaccination strategies. Immunodetection also supports the real-time monitoring of viral mutations, offering critical insights for epidemiological studies and public health policymaking. Advances in high-sensitivity detection tools, such as AIE material-based platforms, have enabled faster and more accurate diagnostics, contributing to the containment of infectious diseases and enhancing global health security. AIE materials, with their unique luminescent properties, show remarkable potential in the immunoassay detection of infectious disease viruses. Their high sensitivity and specificity, combined with immunoassay technologies, provide robust tools for the early diagnosis of viral infections.

Xiong et al. developed a dual-modality immunoassay platform based on AIE signal units, which integrates streptavidin-alkaline phosphatase (SA-ALP), TPE-based AIE probes with enzyme cleavage sites (TPE-APP), and gold nanoparticles as signal elements. When the immunocapture unitcomprising magnetic microbeads, anti-VP1 monoclonal antibodies (mAb-VP1), rabbit polyclonal antibodies (P-Ab), and biotinylated antibodies (Biotin-Ab)captures the target EV71 virus, SA-ALP promotes the hydrolysis of TPE-APP to produce water-insoluble TPE-DMA molecules ( Figure A). These TPE-DMA molecules aggregate in water and emit bright fluorescence, enabling the platform to operate in a ″fluorescence turn-on″ mode with an ultralow detection limit as low as 1.4 copies/μL. Simultaneously, the hydrolysis of TPE-APP mediates the reduction of silver ions, leading to the formation of silver nanoshell on the surface of gold nanoparticles. The formation of these nanoshell induces a significant plasmonic color change, which can be clearly recognized by the naked eye across a wide dynamic range of 1.3 × 10 3 to 2.5 × 10 6 copies/μL ( Figure B and C). Moreover, by coupling the immunocapture unit with suitable antibodies, the platform can be adapted to capture different viral targets, such as H7N9 and Zika viruses, enabling the precise detection of various pathogens ( Figure D and E). Although current studies mainly concentrate on virus detection, it is essential to consider the possible presence of live viruses in waste generated from sample testing. This situation presents a risk of secondary environmental contamination and the potential for virus transmission. Xiong et al. introduced a novel two-step fluorescence immunoassay that employs antibody/streptavidin dual-labeled polystyrene nanobeads in conjunction with biotin-labeled G-quadruplex/hemin DNAzymes exhibiting peroxidase-like activity. This system is designed for the sensitive quantification and efficient inactivation of live Zika virus (ZIKV). The dual-labeled nanobeads specifically target the ZIKV through its E protein and simultaneously accumulate the DNAzymes, resulting in the catalytic oxidation of Amplex Red indicators and the production of enhanced aggregation-induced emission fluorescence signals, achieving a detection limit as low as 66.3 PFU/mL with 100% accuracy. Additionally, the reactive oxygen species generated in situ by oxidized Amplex Red upon irradiation can effectively eliminate the virus. This integrated system for sensitive detection and inactivation enhances our arsenal of viral diagnostic tools and helps mitigate the risk of a viral transmission in the environment.

The global spread of monkeypox has triggered heightened concern over public health in the international community, leading to its declaration as a public health emergency of international concern. The lesions associated with monkeypox primarily manifest as ulcers or pustules on the skin and mucous membranes, containing a high quantity of highly replicative virus particles, which facilitates transmission mainly through close contact with infected individuals. Currently, there are limited clinical imaging diagnostic methods for monkeypox, and existing treatment strategies face numerous deficiencies and challenges.

To address this issue, Tang et al. designed a biomimetic nanosystem (TBD@M NPs), which encapsulates a core of photothermal molecules TPE-BT-DPTQ within polymer nanoparticles that exhibit aggregation-induced emission, and is coated with immune cell-macrophage membranes. In a model using scarification on the tails of mice infected with vaccinia virus as an alternative model for monkeypox, intravenous injection of TBD@M NPs demonstrated precise targeting of the lesions and near-infrared fluorescence imaging capabilities ( Figure A and B). Upon exposure to an 808 nm laser, the photothermal effect effectively eliminated the virus, accelerating healing at the site of the infection. Notably, the suspension of treated lesion tissue did not induce tail infection or inflammatory responses in healthy mice, proving that it effectively blocked viral transmission. This study marks the first demonstration of the potential of nanomedicine in diagnosing and treating monkeypox virus, providing new ideas and research directions for the development of immunodiagnosis and therapeutic strategies in monkeypox clinical applications.

Influenza is one of the most common infectious diseases affecting humans and animals worldwide. The viral envelope contains numerous sugar receptors, among which the sialic acid/sialic acid-related sugar chains found in glycoproteins and glycolipids serve as functional receptor sugar chains for human and animal influenza A viruses. Due to the properties of AIE materials, which allow for the detection of molecular interactions through fluorescence signals, there is a drive to develop a novel biosensor that combines the AIE system with sugars. This biosensor may help determine the specificity of cell surface receptors in recognizing various foreign organisms such as bacteria, viruses, and proteins. Kato et al. designed and synthesized an alkyne-containing TPE derivative, successfully achieving molecular assembly through click chemistry techniques. Utilizing this novel alkyne-based TPE compound, they further synthesized fluorescent oligosaccharide probes with lactose and 6’-sialyllactose as ligands ( Figure A). It shows the fluorescence spectra of influenza virus A/WSN/33 in 10 mM Tris-HCl, pH 7.6, in both the presence and absence of α 2,6sl-TPE ( Figure B). The α 2,6sl-TPE exhibited very weak emission at a concentration of 5 μM. Emission below 400 nm depended on the background luminescence of the 96-well microplate. Upon the addition of influenza virus A/WSN/33, the emission band at 460 nm increased. The study demonstrated that the lactose-containing TPE compound could be used to detect RCA120 lectin, while the 6’-sialyllactose-containing TPE compound was suitable for SSA lectin detection. Additionally, experiments proved that TPE-based fluorescent oligosaccharide probes, when incorporating the 6’-sialyllactose fragment, could function as an ″on″ type fluorescent sensor for the highly sensitive detection of influenza viruses ( Figure C and D). This research provides a new strategy for the development of efficient and specific fluorescent probes and opens new avenues for viral detection.

Applications of AIE Materials in Immunofluorescence Imaging

AIE materials have shown great potential in the application of immunofluorescence imaging in recent years. Immunofluorescence imaging is a technique that combines antigen–antibody specific recognition with fluorescent labeling to visualize the spatial distribution and dynamic behavior of immune molecules. AIE materials possess significant advantages in this field due to their high photostability, high sensitivity, and low background signal. ,

AIE Materials Conjugated with Antibodies for Imaging

AIE materials, when conjugated with antibodies for imaging, combine high-sensitivity optical probes with molecular targeting techniques. They are used in tumor detection, disease diagnosis, and precision imaging. AIE materials exhibit enhanced luminescence efficiency in the aggregated state, allowing for accurate identification of tumor markers when combined with specific antibodies, resulting in high-resolution imaging with low background noise, while also demonstrating good biocompatibility. Research has shown that this technology not only improves the sensitivity and specificity of tumor imaging but also can be integrated with photodynamic therapy for a combined diagnostic and therapeutic approach. Future developments will further optimize material performance, promoting its broad application in precision medicine.

Zhao et al. developed a far-infrared microdot coated with a polyethylene glycol-functionalized polystyrene-maleic anhydride copolymer (PEG–PSMA) and an AIE-active polymer PDFDP as the core. These AIE dots based on AIE polymers demonstrate improved stability compared with traditional small-molecule AIE dots. In the study, copper-free click chemistry was employed to conjugate anti-HER2 antibodies to the AIE dots, achieving targeted recognition of HER2 receptor-overexpressing breast cancer cells ( Figure A). The synthesis of the PEG–PSMA polymer utilized an efficient one-pot method, where the anhydride ring of PSMA exhibited high reactivity toward amines, allowing for effective grafting of Boc-NH-PEG-NH2 onto the PSMA backbone. By deprotecting the Boc group, the exposed amines could further participate in coupling reactions combined with fluorescent labeling for confirmation. Ultimately, the prepared antibody-modified AIE dots (RHA-AIE dots) were able to specifically recognize HER2-positive tumor cells ( Figure B). AIE materials were conjugated with antibodies in the form of nanoparticles, and the doping ratios were meticulously optimized prior to conjugation. Additionally, their stability under varying pH, temperature, and buffer conditions was rigorously validated. It showed good biocompatibility in in vivo experiments as well as a certain therapeutic effect on animal tumor models, providing a novel tool and method for early cancer diagnosis ( Figure C). This research demonstrates that the developed AIEdots, when conjugated with antibodies, effectively target tumor cells with consistency comparable to conventional dyes (Fluor488). However, the photostability of AIEdots is significantly superior to that of conventional dyes. Under continuous irradiation, the fluorescence signals of AIEdots remain stable and detectable, whereas the fluorescence of conventional dyes rapidly decays. These findings further underscore the superior performance and reliability of AIE materials in biomedical applications.

AIE nanoparticles can achieve excellent biocompatibility through chemical modification or physical encapsulation. Additionally, the AIE mechanism can restrict intramolecular movement, effectively suppressing energy dissipation, allowing for the design of AIE photosensitizers (AIE PS) that exhibit high singlet oxygen ( 1 O 2 ) generation efficiency and bright fluorescence in the aggregated state. The synthesized AIE photosensitizer probes or nanoparticles (NPs) have demonstrated capabilities not only for fluorescence imaging but also for guiding photodynamic therapy, showcasing significant potential for applications in the biomedical field. Building on precise imaging in animal models, Wu et al. successfully designed a photosensitizer AIEPS5 with AIE properties that emits far-red/near-infrared (FR/NIR) fluorescence through structural optimization. This photosensitizer can efficiently generate singlet oxygen ( 1 O 2 ) when it is irradiated with a 532 nm laser. By introducing polyethylene glycol (PEG) chains onto the AIEPS5 molecule, they developed an amphiphilic AIEPS5-PEG2000 molecule capable of self-assembling into stably dispersed nanoparticles in water. Further modification with anti-HER-2 nanobodies endowed these nanoparticles with targeted delivery functions ( Figure A and B). The prepared AIEPS5-NPs-NB exhibited an exceptional 1 O 2 generation capability alongside bright FR/NIR fluorescence emission centered at 680 nm ( Figure C and D). Additionally, they displayed extremely low dark toxicity under dark conditions, outperforming the clinical photosensitizer hematoporphyrin used in patient-derived tumor transplant models for PDT. This study not only enhanced the performance of AIEgens in tumor precise imaging ( Figure E) but also increased their cytotoxicity against tumor cells, thereby developing an integrated AIE nanodrug that combines diagnostic and therapeutic functions, providing new insights into the integrated diagnosis and treatment of tumors.

Tang et al. designed and synthesized a novel red fluorescent material with AIE characteristics. This material is based on a conjugated donor–acceptor (D-A) structure, which not only overcomes the fluorescence quenching issue seen in traditional fluorescent molecules in the aggregated state but also exhibits enhanced photostability and excellent two-photon absorption properties. By encapsulation of biocompatible DSPE-PEG 2000 and DSPE-PEG 2000 -COOH, AIE nanoparticles with good dispersion were prepared, and these nanoparticles were functionalized with the antibody cetuximab to enable targeted recognition of the epidermal growth factor receptor (EGFR) ( Figure F). EGFR is commonly overexpressed in tumor cells, such as those found in non-small cell lung cancer, giving these nanoparticles a significant advantage in specific fluorescence imaging of cancer cells. This novel AIE nanoparticle demonstrates bright red fluorescence emission, high photostability, and excellent targeting specificity, making it an ideal tool for tumor diagnosis and detection. This design not only promotes the application of AIE materials in the biomedical field but also provides new possibilities for precise imaging of EGFR-overexpressing tumors like non-small cell lung cancer.

Compared with traditional ELISA colorimetric methods that only provide absorbance signals, FLISA methods have significant advantages in terms of detection limits. Despite the theoretical potential for higher signal sensitivity from fluorescent signals, a crucial question remains: can the aggregated state of AIE molecules or AIE dots remain stable in complex and interfering environments to provide reproducible fluorescence signals? We are particularly concerned about potential issues such as inconsistent aggregation morphology and size after the probe response, as precise material preparation is crucial. When using AIE dots as the fluorescence signal source for detection, it is imperative to strictly control the preparation process of AIE dots to ensure uniformity in their size and morphology. Research has successfully utilized microfluidic technology to precisely prepare AIE dots with stable particle size and resistance to environmental interference. , When AIE molecules aggregate, their morphology is regulated by various factors, including incubation time, temperature, concentration, pH value, ionic strength, etc. Studies have shown that by optimizing the structure of AIE molecules through molecular engineering and combining with the development of automated instruments, and strictly following these conditions during the preparation process, the aggregated state of AIE can be effectively controlled. The obtained AIE aggregates exhibit consistent size and morphology between batches, thus, producing reproducible signals. This improvement will make detection results more reproducible and stable in practical detection processes, not only enhancing the performance of AIE materials but also providing a more reliable foundation for their applications in fields such as biological imaging and chemical sensing.

AIE Materials Are Used for Immune Cell Imaging

The relationship between liver cancer and tumor-associated macrophages (TAMs) is highly interconnected. TAMs predominantly originate from resident macrophages in the liver and monocytes in the bloodstream. In the context of liver cancer, there is often an elevated proportion of TAMs, which exhibit the capacity to secrete growth factors and immunosuppressive factors that foster tumor cell proliferation while inhibiting antitumor immune responses, thus facilitating tumor growth and metastasis. Furthermore, TAMs interact with other cellular components within the liver cancer microenvironment, creating a milieu conducive to tumor development. Chronic inflammatory conditions, such as hepatitis and liver cirrhosis, can also induce the accumulation of TAMs, consequently heightening the risk of liver carcinogenesis. Therefore, therapeutic strategies targeting TAMs have garnered attention in the hope of enhancing treatment outcomes for liver cancer patients. However, the intricate molecular mechanisms through which TAMs contribute to immune evasion in liver cancer remain poorly defined, significantly impeding the advancement and application of immunotherapy. Cell-to-cell interactions within the tumor microenvironment (TME) are essential for the occurrence of immune evasion. Among these interactions, the cooperative modulation between TAMs and cancer-associated fibroblasts (CAFs) is recognized as a pivotal factor driving immune evasion in liver cancer. Although certain studies have documented the critical roles of CAFs and TAMs in tumor progression, the specific intercellular signaling pathways and mechanisms underlying their interaction have yet to be fully elucidated. Particularly, the synergistic effects of TAMs and CAFs during the progression of liver cancer have been inadequately explored, with detailed molecular mechanisms remaining unresolved.

Tang et al. developed a small molecular fluorescent probe, TPEARG, which can specifically target arginase (ARG) ( Figure A). The close relationship exists between arginase and TAMs. Specifically, M2-like TAMs, a subtype of TAMs with anti-inflammatory and immunoregulatory properties, are capable of expressing arginase 1 (Arg1). This enzyme depletes arginine in the microenvironment, thereby impeding T-cell proliferation and their ability to kill tumor cells. In other words, by modulating the levels of arginine in the microenvironment, arginase indirectly facilitates tumor immune evasion and progression. Through the enzymatic cleavage of TPEARG by arginase, the probe emits a bright fluorescent signal, enabling high-sensitivity imaging detection of dynamic changes in ARG both in cells and in vivo. To further investigate the role of ARG in the tumor microenvironment, particularly its function in TAMs, the researchers combined TPEARG with an imaging strategy to assess the activation levels of cancer-associated fibroblasts (CAFs). The experimental results indicated that as the expression level of ARG in TAMs increased, the proline content within the cells significantly rose. Previous studies have shown that CAFs promote immune evasion by downregulating the JAK-STAT signaling pathway, which plays a key role in immune evasion across various cancer cell types. This study further validated this mechanism, revealing that elevated proline levels significantly enhanced the activation status of CAFs, subsequently leading to the upregulation of immune evasion markers in liver cancer. Through signaling pathway analysis, the research unveiled the cooperative mechanism between TAMs and CAFs in immune evasion in liver cancer. To simultaneously monitor the dynamic changes of TAMs and CAFs, the researchers developed a dual-mode imaging strategy that integrates the arginase-specific probe (TPEARG) and the CAF-specific probe (Cy-FAP). This strategy was successfully applied in both in vitro cellular experiments and in vivo models to achieve real-time monitoring of the ARG expression and CAF activation status. Furthermore, based on the established CAF-specific imaging platform, the researchers delved into the molecular mechanisms by which arginase promotes immune evasion in liver cancer. The findings revealed that TAMs increased proline levels by expressing high levels of arginase, thereby activating CAFs; in turn, CAFs exacerbated TAM-mediated immune evasion in liver cancer through the secretion of immunosuppressive molecules ( Figure B). This research not only provides robust tools for studying the function of arginase but also uncovers new mechanisms of its role in immune evasion, offering potential new strategies for targeted therapy in liver cancer. From a medicinal chemistry perspective, this study presents new ideas and methods for investigating the regulatory mechanisms of the tumor microenvironment through the design of molecular probes and signaling pathway analysis.

The TAMs play a critical role in promoting tumor development within the tumor microenvironment and have been regarded as a promising target for cancer therapy in early clinical studies. Therefore, the development of therapeutic diagnostic systems that can specifically target, image, and even eliminate TAMs holds significant clinical value. The research team led by Tang synthesized a novel therapeutic diagnostic probe, designated TPE-Man, which aims for specific recognition by conjugating mannose moieties with a red-light-emitting AIE active photosensitizer ( Figure C). TPE-Man effectively targets the mannose receptors that are overexpressed on TAMs through mannose-receptor interactions, facilitating high-contrast fluorescence imaging of mannose receptor-positive TAMs. Histological analysis of tumor slices from mice further demonstrated the exceptional targeting specificity of TPE-Man ( Figure D). In summary, TPE-Man represents the first small molecular therapeutic diagnostic probe aimed at TAMs, exhibiting significant advantages, such as low cost, high targeting specificity, enhanced fluorescence imaging, and efficient photodynamic ablation.

Application of AIE Materials in Cancer Immunotherapy

AIE materials have demonstrated promising applications in cancer immunotherapy, primarily in enhancing immune responses, targeted drug delivery, regulating immune cell activity, and optimizing the tumor microenvironment ( Table ). Leveraging their unique optical properties and excellent biocompatibility, AIE materials serve not only as efficient imaging probes to enable real-time monitoring of immunotherapy but also as drug delivery platforms that enhance therapeutic efficacy. Additionally, AIE materials contribute to improving the tumor microenvironment by restoring the immune cell functionality and promoting robust antitumor immune responses.

Photothermal AIEgens for Immunotherapy

PTT is a tumor treatment method that utilizes the optical thermal effects of photothermal conversion materials, which generate heat under irradiation at specific wavelengths to effectively destroy tumor cells. Once activated, photothermal agents absorb light energy and convert it into heat energy, significantly increasing the temperature of tumor cells and inducing apoptosis or necrosis. Compared to traditional therapeutic methods, PTT offers advantages such as noninvasiveness, strong targeting ability, and minimal side effects.

In PTT, combining immunotherapy can further enhance its antitumor efficacy. PTT not only directly destroys tumor cells but also induces immunogenic cell death (ICD), leading to the release of tumor antigens and the activation of the immune response. Additionally, cytokines and other immune signals released during the treatment process strengthen the immune activity within the tumor microenvironment, helping the immune system recognize and eliminate distant tumor cells. This synergistic strategy of combining PTT and immunotherapy not only improves the efficacy of tumor treatment but also offers potential for long-term control of recurrent and metastatic cancers.

AIE materials exhibit significant advantages in photothermal-driven immunotherapy. Their efficient photothermal conversion capability enables them to generate localized heat under NIR light irradiation, directly destroying tumor tissues and releasing tumor-associated antigens to activate the immune system. The intrinsic fluorescence properties of AIE materials allow real-time monitoring of the therapeutic process, facilitating precise control. ,

Through functional modifications, AIE materials can achieve tumor-targeting capabilities and enhance therapeutic outcomes when combined with immunomodulators. Furthermore, their excellent biocompatibility and low toxicity make them particularly suitable for clinical applications, offering a promising platform for advancing photothermal immunotherapy. The aggregation-caused quenching effect of conventional fluorescent molecules and their limited penetration in the near-infrared II (NIR-II) region hinder their application in imaging and photoactivated therapy. To address this limitation, Yu et al. designed and synthesized a novel NIR-II molecule (TST) with AIE properties and PTT capabilities. To further enhance its fluorescence efficiency and therapeutic effects, they coassembled TST with a camptothecin prodrug (CPT-S-PEG) and an immune checkpoint inhibitor (AZD4635) into nanoparticles. The strong interaction between camptothecin and TST restricted the intramolecular rotation of TST, suppressing nonradiative decay and significantly enhancing fluorescence emission. Upon uptake by cancer cells, redox-sensitive CPT-S-PEG degraded, causing the nanoparticles to disassemble. The release of TST relieved the constraints imposed by camptothecin, increasing nonradiative decay and enhancing photothermal conversion efficiency. Under PTT, cancer cells underwent ICD, releasing a large amount of ATP into the tumor microenvironment, which facilitated the recruitment of immune cells. However, excess ATP was converted into the immunosuppressive molecule adenosine through the CD39-CD73-A2AR pathway. At this point, AZD4635 released from the photothermally decomposed nanoparticles effectively blocked this immunosuppressive pathway, achieving a synergistic effect of PTT, chemotherapy, and immunotherapy. This innovative approach offers a novel strategy for tumor treatment ( Figure A). Due to its ability to synergistically enhance therapeutic efficacy against primary tumors and distant metastatic tumors, combined photothermal-immunotherapy has emerged as a research hotspot in cancer treatment.

Yan et al. designed and developed a multifunctional therapeutic agent, TPA-BT-DPTQ, based on a benzothiophene structural unit. This agent exhibits AIE properties and enables simultaneous fluorescence imaging (FLI), photoacoustic imaging (PAI), photothermal imaging (PTI), and tumor ablation in the NIR-II region. Further experiments demonstrated that TPA-BT-DPTQ nanoparticles mediated PTT, effectively destroying primary tumors and inducing ICD ( Figure B). This triggered an antitumor immune response, thereby inhibiting the growth of distant tumors. Moreover, when PTT was combined with the immune checkpoint inhibitor programmed death-ligand 1 (PD-L1) antibody, the efficacy of immunotherapy was further enhanced, effectively preventing cancer recurrence and metastasis. This integrated strategy represents a promising avenue for cancer treatment, providing both precision imaging and therapeutic benefits.

To address the complexity and heterogeneity of tumors, combination therapy has emerged as an optimal strategy to simultaneously eliminate primary tumors and suppress the growth of distant tumors. Liu’s research group developed a novel AIE photosensitizer, T-TBBTD, designed with a donor–acceptor–donor (D-A-D) structure ( Figure ). This molecular design enhances molecular torsion and extends its emission wavelength in the NIR-II window, providing precise multimodal imaging capabilities and exceptional PTT and PDT performance. These features hold great promise for advancing molecular therapies in cancer treatment. The NIR-II fluorescence imaging modality has become a critical tool in tumor imaging due to its superior spatial and temporal resolution and deeper tissue penetration capabilities. Liu’s team further developed AIE@R837 nanoparticles with antitumor photoimmunotherapeutic properties. Upon localized irradiation, these NPs generate significant heat and singlet oxygen ( 1 O 2 ), directly killing tumor cells and inducing ICD. Additionally, the release of the immune adjuvant R837 from the NPs amplifies antigen presentation and stimulates durable, protective antitumor immunity. In bilateral 4T1 tumor models, this photoimmunotherapy approach effectively eradicated primary tumors and significantly inhibited the growth of distant tumors. The method highlights the synergistic effects of phototherapy and immunotherapy, offering a transformative and promising strategy for advanced cancer treatment and clinical applications.

Enhancing tumor immunogenicity is key to addressing the challenges of low therapeutic efficacy and the recurrence or metastasis of cancers. Strategies such as promoting tumor antigen presentation, modulating the tumor microenvironment to reduce immune suppression, using cancer vaccines to stimulate the immune system, combining chemotherapy or radiotherapy to induce antigen release, and enhance immunogenicity have proven effective in improving immune responses. These methods not only boost therapeutic outcomes but also mitigate the risks of recurrence and metastasis. For example, Tang’s research group developed a thermoresponsive nanoparticle system comprising a photothermal agent and a click reaction initiator to enhance the efficacy of cancer immunotherapy. They synthesized a nickel-based bithiophene PTA with superior near-infrared absorption and efficient photothermal conversion capabilities. These PTAs were incorporated into thermoresponsive nanoparticles, generating heat under light activation to induce phase transitions, which facilitated the release of chemotherapeutic agents. Additionally, these nanoparticles could react with amino groups of functional proteins, enabling the synergistic effects of PTT and chemotherapy. Crucially, PTT-induced ICD released reactive molecules that further amplified immune responses. This synergistic approach effectively suppressed the growth of primary tumors and activated an immune response against distant tumors. Such a combination strategy represents a promising and efficient solution for clinical cancer immunotherapy ( Figure ).

Photodynamic AIEgens for Immunotherapy

PDT is a minimally invasive treatment modality that combines photosensitizers (light-sensitive molecules) with specific wavelengths of light to treat tumors and other pathological conditions. The process begins with the administration of a photosensitizer, which selectively accumulates in tumor tissues. After a waiting period to allow for absorption, the tumor area is illuminated with a specific wavelength. This activates the photosensitizer, leading to the generation of reactive oxygen species (ROS), particularly singlet oxygen, which induces damage to tumor cells, the surrounding vasculature, and the tumor microenvironment. This damage results in tumor cell apoptosis or necrosis. An additional benefit of PDT is its ability to stimulate an immune response, promoting long-term tumor control by enhancing the immune system activity against cancer cells. PDT offers several advantages over traditional therapies such as surgery, radiotherapy, or chemotherapy. It is less invasive, has fewer systemic side effects, allows for precise targeting of tumor tissues, and promotes faster recovery.

Photosensitizers play a crucial role in photodynamic therapy, not only in generating ROS but also in guiding the light irradiation area through their fluorescence signals. However, enhancing the photosensitization efficiency and imaging sensitivity of photosensitizers remains a significant challenge. One of the main issues is that most conventional photosensitizers (such as porphyrins, rose bengal, etc.) possess planar structures, which are prone to aggregation-caused quenching (ACQ) effects due to strong π–π interactions in aggregates. This leads to reduced fluorescence signals and compromised photosensitization at high concentrations or in aggregate states, particularly when photosensitizers accumulate in diseased tissues. Additionally, the continuous fluorescence emission of traditional photosensitizers can interfere with the imaging sensitivity, making it difficult to distinguish target areas from background signals. Therefore, there is a strong demand for the development of new photosensitizers with an enhanced photosensitization ability and specific fluorescence activation capabilities.

The discovery of AIEgen provides a promising solution. AIE is a phenomenon where fluorophores are nonemissive in their molecular state but exhibit significantly enhanced fluorescence in their aggregated or solid state. AIEgens generally possess twisted or propeller-like structures, which restrict the molecular motions in the molecular state and reduce nonradiative energy loss. Upon aggregation, these molecules suppress nonradiative decay pathways and activate radiative decay pathways, leading to strong fluorescence emission. The unique optical properties of AIEgens make them ideal candidates for fluorescence probes that can be activated by target-mediated aggregation or the restriction of intramolecular motions (RIM). Furthermore, with sophisticated molecular design, AIE photosensitizers can be engineered to exhibit excellent photosensitization properties and controllable generation of various ROS types, catering to different application needs. Unlike traditional ACQ photosensitizers, AIE photosensitizers with twisted structures exhibit enhanced ROS production in their aggregated state, which further broadens their applications in PDT. In antibacterial applications, the advantages of AIE materials lie in their ability to target specific bacterial characteristics. By aggregation, AIE materials enhance their photosensitivity, increasing the efficiency of ROS generation upon contact with bacteria. AIE materials exhibit significant antibacterial effects against both Gram-positive and Gram-negative bacteria. Furthermore, the targeted use of AIE materials in conjunction with bacteriophages offers selectivity, reducing damage to surrounding healthy cells and beneficial bacteria. This makes AIE materials a promising option for clinical disinfection and infection treatment. Combining their excellent imaging capabilities with outstanding antibacterial effects, AIE materials in photodynamic therapy not only aid in cancer treatment but also provide new strategies for controlling bacterial infections. , With further research, AIE materials are expected to demonstrate significant potential in a broader range of antibacterial and anticancer applications.

PDT is effective not only by directly killing tumor cells but also by inducing immune activation. When photosensitizers are activated in the tumor site, ROS are produced, leading to cell damage, death, and the release of various antigens. These antigens can stimulate the body’s immune response, promote the maturation and activation of dendritic cells, and enhance T cell infiltration. In addition, the dead tumor cells can release pro-inflammatory cytokines, further attracting and activating immune cells such as macrophages and T cells, thereby improving the body’s ability to recognize and attack tumors. This immune activation not only strengthens control over primary tumors but also has the potential for immune memory against metastatic disease, providing long-term antitumor effects. Therefore, the ability of photodynamic therapy to stimulate immune responses has significant clinical implications. ,

The main challenge in the treatment of multiple myeloma lies in the damage to the immune microenvironment, which leads to tumor relapse and the progression of extramedullary disease. , Feng et al. proposed an innovative approach using bovine serum albumin (BSA) nanoparticles loaded with AIE photosensitizers (termed BSA/TPA-Erdn) to enhance ICD and enable immunotherapy. This strategy effectively transforms cold tumors into hot tumors and thereby restores the immune microenvironment in multiple myeloma. By embedding the AIE photosensitizer into the hydrophobic domains of BSA, the geometric stability of the molecule was significantly enhanced, leading to a substantial increase in the generation of ROS, which is crucial for inducing an effective ICD immune response. In a NOD-SCID IL-2 receptor γ-deficient mouse model established with monocytes from multiple myeloma patients, the results showed that BSA/TPA-Erdn could simulate the maturation of human dendritic cells and enhance polarization and differentiation signals, demonstrating a good immune therapeutic effect. Notably, this study was the first to confirm that BSA/TPA-Erdn could significantly reverse T cell senescence, which is a major challenge in multiple myeloma treatment. Furthermore, BSA/TPA-Erdn effectively recruited more functional T lymphocytes into the multiple myeloma tumor site. Therefore, BSA/TPA-Erdn not only successfully repaired the immune microenvironment of multiple myeloma but also exhibited significant tumor eradication ability, providing new directions for clinical multiple myeloma therapy ( Figure ).

Bladder cancer is characterized by its high recurrence rate and multifocal nature. In recent years, the ICD of cancer cells has been recognized as an emerging strategy to enhance tumor cell immunogenicity and boost cancer immunotherapy. Although PDT based on photosensitizers has been proven to induce ICD in cancer cells, photosensitizers with sufficient ICD-inducing capability are still relatively scarce, and there is limited research on the development of efficient ICD-inducing photosensitizers for bladder cancer cells. Liu et al. synthesized a novel AIE photosensitizer targeting the endoplasmic reticulum (ER) (DPASCP-Tos), which effectively localizes within the ER and promotes the accumulation of ROS in this region, thereby efficiently inducing ICD in bladder cancer cells. Moreover, bladder cancer cells treated with ER-targeted PDT could serve as a therapeutic cancer vaccine, inducing a strong antitumor immune response. Preinoculation of bladder cancer cells treated with DPASCP-Tos under light stimulation promoted dendritic cell (DC) maturation and effectively expanded CD8 + T cells targeting tumor antigens in vivo, protecting mice from recurrence of subsequent orthotopic bladder tumors and significantly prolonging animal survival. In conclusion, the ER-targeted AIE photosensitizer developed in this study significantly enhanced the ICD of bladder cancer cells through ROS-induced oxidative stress in the ER and transformed them into a therapeutic vaccine, strengthening the immunogenicity against orthotopic bladder cancer. This provides important theoretical support and practical value for the treatment of bladder cancer ( Figure ).

In the field of biomedicine, the development of safe and efficient targeted drug delivery systems holds significant research value and application prospects. In recent years, remarkable progress has been made in bionic nanodrug delivery platforms centered on AIE molecules. These intelligent delivery systems, achieved through the precise assembly of AIEgens and natural biological carriers, demonstrate multiple advantages: exceptional biosafety, prolonged in vivo circulation half-life, precise lesion-targeting capabilities, and potential immunomodulatory functions. Research indicates that various biologically derived carriers, such as cell membrane-mimetic carriers, exosome delivery systems, and microorganism-based carriers, can be utilized for the efficient delivery of AIE molecules. Leveraging their unique biological properties, these carriers can endow therapeutic systems with specific functional characteristics, thereby effectively activating antigen presentation pathways and significantly enhancing the body’s antitumor immune response capabilities.

DC-derived small extracellular vesicles (DEVs) are considered a promising alternative to DC vaccines; however, DEV-based immunotherapies have shown limited efficacy in clinical applications. The Wang research group proposed a simplified strategy, using DCs as cellular reactors to efficiently amplify the production of excreted DEV-like AIE nanoparticles for synergistic photodynamic immunotherapy. These excreted DEV-AIE NPs not only retained the immunoregulatory proteins of the parent DCs, which could activate T cells, but also loaded the AIE photosensitizer MBPN-TCyP, which selectively accumulates in the mitochondria of tumor cells, effectively affecting ICD. Ultimately, the synergistic photodynamic immunotherapy with DEV-AIE triggered a significant immune response, effectively eliminating primary tumors, metastatic tumors, and distant metastases. Moreover, the immune-functionalized DEV-AIE NPs significantly inhibited cancer stem cells (CSCs) in 4T1 and CT26 solid tumors. This study presents a convenient strategy for generating EV-biomimetic nanoparticles from cells, demonstrating that the combination of DEVs and AIE photosensitizers holds significant potential in the development of clinical anticancer nanovaccines ( Figure A).

Surgery is the traditional approach to tumor treatment, but postoperative recurrence remains a challenging issue. Immunotherapy, by enhancing the immune system’s ability to clear residual tumors, helps reduce recurrence rates. However, the low response rate of traditional immunotherapeutic drugs and their nonspecific targeting limit their efficacy. Xia et al. developed a novel disguised nanoparticle (M@PFC) designed for more efficient postoperative tumor treatment. M@PFC consists of nanoparticles wrapped in macrophage membranes, with a core containing the AIE photosensitizer PF3-PPh3 and the immune adjuvant CpG. Specific proteins on the macrophage membrane interact with the vascular cell adhesion molecule-1 (VCAM-1) on tumor cells, promoting the accumulation of M@PFC at the tumor site while avoiding rapid clearance by the immune system and prolonging circulation time. PF3-PPh3 efficiently generates ROS under light irradiation and ICD in tumor cells. The tumor-internal enrichment of CpG further stimulates tumor cells to secrete immune factors, significantly enhancing the ICD effect. This synergistic strategy, combining AIE PDT with CpG immunotherapy, not only significantly delayed postoperative tumor recurrence but also activated systemic antitumor immune responses. The M@PFC nanoparticles, by integrating the advantages of photodynamic therapy and immunotherapy, provide an efficient new strategy for treating postoperative tumor recurrence, demonstrating the potential for synergistically activating the immune system and offering new directions for the development of therapeutic nanodrugs ( Figure B).

AIEgens Induce Immune Cell Polarization

Immune cell polarization refers to the process by which immune cells differentiate into different functional types in response to changes in the microenvironment and external signals. This process plays a key role in maintaining the immune balance and responding to various pathogens, tumors, and autoimmune diseases. Taking macrophages as an example, they can polarize into the M1 or M2 types. M1 macrophages primarily attack pathogens and tumor cells by releasing pro-inflammatory factors, exhibiting strong antitumor and anti-infection abilities. In contrast, M2 macrophages are mainly responsible for tissue repair and maintenance, possessing anti-inflammatory and tissue-healing functions. Another example is T cells, especially CD4 + T cells, which can polarize into subtypes such as Th1, Th2, or Th17, each responsible for different immune responses. The polarization of immune cells is regulated by a variety of factors, including cytokines, the tumor microenvironment, pathogen characteristics, and interactions with other immune cells. By appropriately modulating the polarization state of immune cells, the immune response to diseases can be enhanced, improving the effectiveness of immunotherapy. Therefore, understanding and manipulating immune cell polarization are crucial for developing novel therapeutic strategies targeting tumors, infections, and autoimmune diseases.

Li et al. synthesized three D–A structured AIEgens with varying ROS generating efficiencies by modulating the electron-withdrawing ability of the acceptor. This study elucidates the relationship between the type and efficiency of ROS and the efficacy of PDT in tumor treatment. The tTDCR nanoparticles, which exhibit the highest ROS generating efficiency, demonstrate exceptional capability in reprogramming M0 and M2 macrophages into the antitumor M1 phenotype through the activation of NF-κB signaling pathways ( Figure ). Notably, we discovered for the first time that the extracellular ROS generated from the type I mechanism plays a critical role in this process rather than the contributions from the type II mechanism. In vivo experiments further confirm that tTDCR nanoparticles can serve as photosensitizers for PDT cancer immunotherapy, effectively re-educating TAMs toward the M1 phenotype. By utilizing tTDCR nanoparticles as the photosensitizer in a single PDT treatment, we achieved complete tumor elimination without recurrence within 20 days, even in the absence of any synergistic incorporation of immune checkpoint inhibitors or immune adjuvants. We speculate that this is due to the type I mechanism overcoming the hypoxic limitations of the tumor microenvironment. Consequently, the successful demonstration of this photosensitizer design for PDT cancer immunotherapy and the clarification of its underlying mechanisms will inspire new opportunities for the development of more effective photosensitizers for advanced therapeutic applications.

Cancer immunotherapy has attracted significant attention for its ability to provide sustained therapeutic effects, precise targeting, and the effective eradication of tumor cells. However, its clinical efficacy is often hampered by tumor heterogeneity and the complex immunosuppressive microenvironment, characterized by a high prevalence of M2 macrophages and various immune checkpoints (ICs). , Cai et al. developed two type-I AIE photosensitizers with varying efficiencies for generating ROS. They also successfully isolated engineered extracellular vesicles (EVs) from 4T1 tumor cells, which express the immune checkpoint Siglec-10. These engineered EVs were subsequently combined with a lipid-based nanosystem loaded with an AIE photosensitizer, resulting in the formation of SEx@Fc-NPs. The type-I AIE photosensitizer within SEx@Fc-NPs generates ROS through PDT, which facilitates the reprogramming of M2 macrophages into M1 macrophages, thereby ameliorating the immunosuppressive landscape of the tumors. Furthermore, the external EV antigens that encompass 4T1 tumor-associated antigens enhance the maturation of dendritic cells, activating diverse populations of tumor-specific T cells to address tumor heterogeneity. Additionally, blockade of Siglec-10 has been shown to reverse macrophage exhaustion, thereby augmenting their antitumor efficacy. This study highlights the promising combinatorial approach of integrating PDT, immune checkpoint modulation, and EV antigens, demonstrating its potential to significantly enhance the effectiveness of tumor immunotherapy and provide novel strategies for mitigating tumor-induced immune suppression and overcoming immune evasion ( Figure ).

Challenges and Prospects of AIE Materiais in Immunology

AIE materials have broad application prospects in the field of immunology, particularly in cancer immune diagnosis and immunotherapy. However, despite their immense potential in basic research, the clinical translation of AIE materials still faces a series of challenges.

Challenges in Clinical Translation

Although AIE materials have demonstrated excellent performance in laboratory research, their translation from the laboratory to clinical applications still faces numerous uncertainties. First, the long-term stability of the AIE materials is a key issue. In in vivo applications, AIE materials need to maintain stable optical performance and structural integrity in complex biological environments, which presents a challenge for their practical use. Due to the unique properties of AIE materials, which differ from traditional fluorescent materials, their stability and degradation rate in the body require further optimization. Both too rapid and too slow degradation could affect their therapeutic efficacy and even lead to potential toxic reactions.

Moreover, the interaction between AIE materials and the immune system is another significant challenge. The interaction of AIE materials with immune cells may affect their function, thus, influencing the effectiveness of immunotherapy. For instance, AIE nanoparticles could alter the activity of immune cells by binding to specific receptors within the immune system, potentially leading to abnormal activation or suppression of immune responses. Therefore, precisely controlling the interaction between AIE materials and the immune system is crucial to ensure therapeutic efficacy while avoiding adverse effects on the immune function. This remains an urgent issue that needs to be addressed.

In the clinical application of PTT or PDT, the potential damage to normal cells caused by AIE materials is a crucial concern that cannot be overlooked. We believe that the bystander cell damage induced by AIE materials in PDT or PTT can be precisely controlled through molecular targeting strategies. Specifically, these photosensitizers, by incorporating tumor microenvironment-responsive groups into their molecular design, such as modifying AIEgens with phosphate groups, can specifically recognize and bind to overexpressed alkaline phosphatase (ALP) on the tumor cell membrane. This targeting design triggers enzyme-driven in situ aggregation at the target site, achieving submicrometer-level precision localization on the surface of tumor cells. Alternatively, nucleic acid-reactive nanoprobes can be cleverly designed to specifically respond to overexpressed microRNA-21 in tumors, initiating a entropy-driven circulation reaction that strictly confine the activated PDT therapy of AIE photosensitizer within target cells. Experimental data strongly demonstrate that these innovative strategies significantly increase the targetability and reduce the adverse effects of PDT/PTT on normal cells, providing a solid foundation for biological safety in in vivo diagnosis and treatment.

Enhancing the Adaptability of Immunotherapy

The low adaptability of tumor immunotherapy is a complex issue related to the tumor microenvironment, immunosuppressive mechanisms, and individual patient differences. AIE materials hold potential for improving the adaptability of tumor immunotherapy.

Currently, immunotherapy (such as PD-1/PD-L1 inhibitors) is effective only for a limited number of tumor types and patients, mainly because tumors have various mechanisms to evade immune surveillance. Immunosuppressive cells (such as myeloid-derived suppressor cells and regulatory T cells) and immunosuppressive molecules (such as PD-L1, TGF-β) in the tumor microenvironment inhibit the activity of immune cells, greatly reducing the effectiveness of immunotherapy. Furthermore, individual differences, such as tumor mutation burden, gene expression profiles, and the patient’s immune system status, also affect the response to immunotherapy.

AIE materials can improve the adaptability of tumor immunotherapy in several ways:

For example, through PDT to enhance ICD, AIE materials can be used as photosensitizers to generate singlet oxygen and other reactive oxygen species under specific wavelengths of light, inducing ICD in tumor cells. ICD is a special form of cell death that can release tumor-associated antigens and immunostimulatory molecules, activating the patient’s own immune system. Combining AIE materials with immune checkpoint inhibitors can enhance the effectiveness of immunotherapy and expand its adaptability. AIE materials can also be designed to target the tumor microenvironment, being sensitive to specific molecules or pH, aggregating and activating in the tumor microenvironment, thereby altering the microenvironment, relieving immunosuppression, and enhancing immune cell infiltration. In addition, AIE materials can be used as drug delivery systems to precisely deliver immunomodulators or chemotherapeutic drugs to the tumor site, reducing side effects and improving efficacy with their optical properties allowing for real-time monitoring of the drug delivery process. AIE materials can also be used for immune cell tracking and regulation, labeling and tracking the distribution and migration of immune cells to gain a deeper understanding of immunotherapy mechanisms, and even designing photoactivatable AIE materials to regulate immune cell activity.

Therefore, the combination of AIE materials and immunotherapy has the potential to overcome the limitations of current immunotherapy and bring hope to more patients. Future research will focus on the development of new AIE materials, optimization of combination therapy regimens, and an in-depth exploration of the interaction mechanisms between AIE materials and the immune system.

Future Outlook

The development of multifunctional AIE materials is an important direction. Future research could integrate imaging, drug delivery, and immune modulation functions into a single material, creating a multimodal diagnosis and treatment platform. By combining current immune therapy technologies such as immune checkpoint inhibitors and cancer vaccines, AIE materials are expected to become an efficient tool to enhance the immune system’s ability to recognize and attack tumors.

AIE materials, leveraging their unique optical properties, are opening up new possibilities for personalized and precision medicine. Their high brightness in the aggregated state, low photobleaching, and excellent biocompatibility make them ideal tools for dynamic bioimaging and monitoring. For instance, in cancer treatment, AIE materials can specifically bind to the tumor microenvironment through targeted modifications, enabling real-time tracking of immune cell dynamics. This provides physicians with individualized treatment feedback, allowing for the optimization of radiotherapy or chemotherapy dosages and regimens. Such real-time monitoring capabilities not only significantly enhance treatment efficacy but also effectively reduce the risk of side effects caused by inappropriate dosages in traditional therapies. In the field of precision medicine, the application of AIE materials extends further to the highly sensitive detection of disease biomarkers. By the design of AIE probes with specific molecule recognition capabilities (such as nucleic acid- or enzyme-responsive probes), trace biomarkers in blood or tissues, such as tumor-associated antigens or inflammatory factors, can be accurately sensed and analyzed. Combined with the rapid analysis of massive amounts of data through artificial intelligence technology, such specific and sensitive detection can provide patients with early diagnosis and prognostic assessment, supporting the development of personalized treatment plans. These advantages of AIE materials demonstrate their immense potential in advancing precision medicine.

The translation of AIE materials from the laboratory to clinical applications requires the addressing of issues related to stability and the evaluation of long-term effects. Optimizing the metabolic pathways and immune compatibility of AIE materials in vivo is a crucial step to ensure their safety and efficacy. At the same time, close collaboration with clinicians and regulatory agencies will help establish standardized production and testing processes to meet clinical and regulatory requirements. With the development of precision medicine, the role of AIE materials in personalized immunotherapy is highly anticipated. By accurately characterizing the tumor microenvironment, AIE materials can assist in designing more targeted treatment strategies that not only improve therapeutic outcomes but also reduce damage to normal tissues. In summary, the technological advancements of AIE materials and interdisciplinary collaboration will accelerate their clinical application in cancer immunology, advancing immune diagnosis and therapy into a new phase.

Conclusion

AIE materials, with their significantly enhanced optical emission characteristics in the molecular aggregated state, have shown broad application prospects in the field of cancer immunology. AIE materials not only improve the sensitivity and specificity of immune responses but also play an important role in the early diagnosis of cancer, immunofluorescence imaging, and the evaluation of immunotherapy. At the same time, AIE materials can serve as vaccines in the immunotherapy process, enhancing the efficacy of treatment and providing new approaches to cancer therapy. Although AIE materials still face certain challenges in terms of biocompatibility, immunotoxicity, and clinical translation, with continuous optimization of material design and technology, the application of AIE materials in cancer immunology will become increasingly widespread, and they are expected to become important tools for disease diagnosis and treatment in the future.

Acknowledgments

The authors are thankful for the support of the National Natural Science Foundation of China (22274106), the Program of Suzhou Innovation and Entrepreneurship Leading Talents (ZXL2022513) and startup funds from Soochow University.

X.H. conceived the original idea for this study. L.Y. wrote the manuscript. L.H.X. and X.H. revised the manuscript.

The authors declare no competing financial interest.

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