Application of aggregation-induced emission materials in gastrointestinal diseases

Abstract

Aggregation-induced emission (AIE) is a phenomenon characterized by certain fluorescent molecules that exhibit weak or no luminescence in solution but demonstrate significantly enhanced luminescence upon aggregation. Accordingly, AIE materials have successfully addressed the limitations associated with aggregation-caused quenching effects and have made significant progress in the application of various fields of medicine in recent years. At present, the application of AIE materials in gastrointestinal (GI) diseases is mainly in GI imaging, diagnosis and treatment. In this review, we summarize the applications of AIE materials in GI pathogens and GI diseases, including inflammatory bowel disease and GI tumors, and outline combined treatment methods of AIE materials in GI tumor therapy.

Key Words: Aggregation-induced emission luminogens; Gastrointestinal pathogens; Inflammatory bowel disease; Gastrointestinal cancer; Photodynamic therapy

Core Tip: Scientists have found extensive applications for aggregation-induced emission (AIE) materials throughout numerous fields. With continuous innovation and development, AIE materials have demonstrated great potential in the imaging, diagnosis, and treatment of various diseases. This article provides a comprehensive overview of the application of AIE materials in gastrointestinal pathogens and diseases, including inflammatory bowel disease and gastrointestinal tumors, such as oral cancer, esophageal cancer, gastric cancer, and colorectal cancer.

INTRODUCTION

The gastrointestinal (GI) tract is an organ system that includes all of the anatomical structures from the mouth to the anus, specifically the esophagus, stomach, small intestine, and large intestine[1]. GI diseases refer to a series of disorders affecting various organs within the GI tract. These include inflammatory GI diseases such as gastritis, appendicitis, ulcerative colitis, and Crohn's disease, as well as GI cancers like oral cancer, esophageal carcinoma (EC), gastric carcinoma (GC), and colorectal cancer (CRC)[1]. Within the GI tract, challenging conditions such as pH fluctuations and the presence of proteolytic enzymes can lead to structural changes or degradation, potentially compromising the effectiveness of treatments for GI diseases[2].

The aggregation-induced emission (AIE) phenomenon was first proposed by Luo et al[3] at the Hong Kong University of Science and Technology in 2001. Specifically, hexaphenylsilole (HPS) exhibits weak fluorescence when dissolved in acetonitrile; however, its fluorescence is significantly enhanced during precipitation in a poor solvent due to decreased solubility. Materials with AIE characteristics, including small molecules, polymers, and nanoparticles (NPs) like HPS, are termed AIE materials. AIE luminogens (AIEgens) are a specific subset of AIE materials that are luminescent molecules. These are typically organic small molecules with defined structures, such as tetraphenylethylene (TPE) and its derivatives. AIEgens are primarily used in fluorescent probes, bioimaging, and chemical sensing. They overcome the limitations of aggregation-caused quenching (ACQ), enabling strong fluorescence in the aggregated state and the generation of large amounts of reactive oxygen species (ROS) upon illumination. As shown in Figure 1, this property enhances both imaging and therapeutic effects. AIEgens are distinguished by their high brightness, high sensitivity, versatility, and good biocompatibility. Moreover, AIEgens can serve as drug carriers and be combined with various therapies to enhance drug delivery efficiency[4]. Compared to traditional technologies, AIEgens offer more accurate, efficient, and safe diagnosis and treatment options, demonstrating broad application prospects in the biomedical field[5,6].

Figure 1 Aggregation-induced emission luminogens (AIEgens) overcomes the aggregation-caused fluorescence quenching effect, enhancing luminescence efficiency at high concentrations. Upon light exposure, they generate reactive oxygen species through a series of reaction processes. A: The common fluorescent dye fluorescein exhibits fluorescence quenching in the aggregated state, while the classic aggregation-induced emission (AIE) molecule tetraphenylethylene overcomes the aggregation-caused fluorescence quenching effect and shows enhanced fluorescence at high concentrations; B: AIEgens generate various reactive oxygen species upon light irradiation. AIEgens: Aggregation-induced emission luminogens; AuNPs: Gold nanoparticles; TPE: Tetraphenylethylene; ACQ: Aggregation-induced fluorescence quenching. Created in Figdraw, and the compound structures were drawn using KingDraw.

Studies have demonstrated that AIEgens can detect GI cancer cells and exhibit high fluorescence stability under different pH conditions[7,8]. Consequently, AIEgens present significant potential for application in the imaging, diagnosis, and treatment of GI diseases. This article will summarize the applications of AIEgens in GI pathogens and diseases, including inflammatory bowel disease (IBD) and GI tumors. Furthermore, we summarize the combined treatment methods of AIEgens in GI tumor therapy.

AIEGENS FOR DETECTION OF INTESTINAL PATHOGENS

Intestinal microbiota dysbiosis represents a crucial etiological factor for intestinal diseases[9]. Hence, the detection of intestinal pathogens is critically important for both the prevention and treatment of these conditions. Salmonella typhimurium (S. typhimurium), a foodborne GI bacterial pathogen, has the highest incidence rate among Salmonella infections. Infection can lead to systemic illnesses and severe food poisoning, which are associated with a relatively high mortality rate[10]. For the detection of S. typhimurium, Li et al[11] developed a bidirectional complementary enhanced immunochromatographic test strip (ITS) with opposite signal readings in colorimetric and fluorescent modes. This strip encapsulates AIEgens within nanosilica to improve the hydrophilic interaction between the AIEgens and target antibodies. It also immobilizes the nanosilica containing AIEgens directly onto the nitrocellulose membrane in the ITS, thereby enhancing the fluorescent signal. Simultaneously, using a sandwich immunoassay structure, the colorimetric signal is enhanced by clustered gold NPs (AuNPs) encapsulated within nanobowls, while the fluorescent signal is quenched. This generates a dual-signal response, combining both colorimetric and fluorescent signals, enabling the effective detection of S. typhimurium[11].

Human enterovirus 71 (EV71) is a positive-strand RNA virus that belongs to the Enterovirus genus within the Picornaviridae family. It is recognized as the primary causative agent of severe hand-foot-and-mouth disease in infants and young children[12]. Therefore, developing sensitive and accurate clinical diagnostic methods for this virus is crucial to prevent the spread of EV71 and subsequent disease outbreaks. Xiong et al[13] have designed a water-soluble multifunctional AIEgen known as TPE-APP, which has been conjugated to an immunoassay system. This multifunctional AIEgen contains an enzyme cleavage site that can be hydrolyzed by virus-immunobridged alkaline phosphatase, leading to the production of a highly emissive AIE polymer. Simultaneously, silver (Ag) can be reduced in situ, forming a shell on the AuNP surface and producing a distinct color change for easy visual detection. Additionally, magnetic enrichment is employed to enhance the specificity of TPE-APP for EV71 detection[13].

The above studies demonstrate that AIEgens can be utilized for detecting GI pathogens, particularly when combined with AuNPs. As shown in Figure 2, this combination enables clear signals in both colorimetric and fluorescent modes, along with high fluorescence intensity, thereby enhancing the potential of AIEgens in GI pathogen detection.

Figure 2 Dual-correspondence system based on gold nanoparticles and aggregation-induced emission luminogens enhances detection of gastrointestinal pathogens. Due to the aggregation of gold nanoparticles, the colorimetric signal increases, while the fluorescence signal of aggregation-induced emission luminogens decreases due to the inner filter effect, resulting in a bidirectional complementary colorimetric/fluorescent signal response. When combined, they exhibit a more sensitive bimodal immunoassay. AIEgens: Aggregation-induced emission luminogens; AuNPs: Gold nanoparticles. Created in Figdraw.

AIEgens FOR DIAGNOSIS AND TREATMENT OF IBD

IBD is a chronic and complex disorder caused by inflammation of the GI system, which encompasses Crohn's disease and ulcerative colitis[14]. Impaired intestinal barrier function is one of the key etiologies of IBD. Therefore, as shown in Figure 3, IBD can be diagnosed by imaging the intestinal barrier. Xu et al[15] designed and synthesized a novel D-π-A-based far-red emissive AIE active fluorescent probe (PTZB-FR)[15]. After oral administration of PTZB-FR to DSS-treated mice, diffuse probe fluorescence was observed in vivo, indicating intestinal barrier function leakage. In contrast, no fluorescence was observed in the negative control, suggesting that the AIE-based fluorescent probe can detect intestinal barrier function leakage and IBD[15]. Thus, AIEgens can be used to detect intestinal barrier leakage in IBD models and monitor inflammatory sites in real time. Additionally, it has been shown that AIEgens can track inflammatory markers such as hypochlorous acid and superoxide anion[16,17], demonstrating its ability to specifically recognize IBD-related biomarkers (e.g., ROS, enzymes, or inflammatory cells). For example, a fluorescent probe with AIE characteristics can track macrophages for IBD detection. The molecule 2-(2′-hydroxyphenyl)benzothiazole-tetraphenylimidazole-pyridinium (HBTTPIP) can spontaneously aggregate within the cavity of β-glucan particles (GPs) in aqueous solution[18]. Because the pro-inflammatory cytokines produced by macrophage infiltration can disrupt the intestinal barrier by altering tight junction structure and function, macrophages act as indicators for monitoring IBD progression[19]. GPs can be specifically recognized by pathogen recognition receptors expressed by dendritic cells and macrophages[20]. Therefore, HBTTPIP can effectively track macrophages for the diagnosis of IBD[18]. The above studies demonstrate that AIEgens have more intuitive and specific advantages in IBD diagnosis.

Figure 3 Aggregation-induced emission luminogens detect inflammatory bowel disease by intestinal barrier damage or targeting inflammatory markers. After oral administration, aggregation-induced emission luminogens (AIEgens) pass through the mucosal layer through the damaged intestinal barrier site. ¹AIEgens spontaneously aggregate and are retained. ²AIEgens track macrophages, aggregate, and are retained at the inflammatory bowel disease (IBD) site. Fluorescence indicates the IBD site after illumination. AIEgens: Aggregation-induced emission luminogens; IBD: Inflammatory bowel disease. Created in Figdraw.

Furthermore, fluorescence imaging based on AIEgens can guide IBD surgery. Fan et al[21] developed an NIR-II fluorescent AIEgen N,N-Diphenylnaphthalen-1-amine-Benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole (BPN-BBTD) and encapsulated it with the amphiphilic polymer Pluronic F127 into NPs. Due to the retention effect of NPs, the AIEgen accumulates at the IBD lesion site[22]. The results showed that BPN-BBTD NPs can effectively accumulate at the inflammatory site and emit bright NIR-II fluorescence, enabling precise localization of the inflammatory lesion and easy monitoring of disease severity and response to treatment intervention. Finally, Fan et al[21] demonstrated the use of NIR-II fluorescence imaging to guide IBD treatment surgery, successfully removing the lesion site in IBD mice and suturing the normal intestine. This result demonstrates the great potential of AIEgens for clinically guided IBD surgery.

Overall, AIEgens can improve the targeting of IBD inflammatory sites by accumulating at inflammation site to detect IBD or by targeting inflammatory cells and combining with NPs to enhance retention and guide IBD surgery.

AIEgens FOR DIAGNOSIS AND TREATMENT OF GI TUMORS

AIEgens exhibit high sensitivity, enabling the detection of cancer biomarkers (such as proteins, DNA, or metabolites) at extremely low concentrations. AIEgens can be functionalized to bind to specific cancer biomarkers, achieving specific recognition and imaging of cancer cells, as well as real-time monitoring of their distribution and metastasis[23,24].

In addition to early cancer detection, AIEgens can be applied in cancer treatment. Photodynamic therapy (PDT) is an innovative form of radiotherapy and a non-invasive tumor treatment method. PDT utilizes the ROS generated by photosensitizers (PSs) upon exposure to light to disrupt the intracellular redox balance, leading to tumor cell death[25]. As shown in Figure 4, PSs with AIE characteristics (AIE PSs) have shown important prospects in PDT. This is attributed to their strong fluorescence and enhanced ROS generation ability in the aggregated state, which effectively mitigates the aggregation-induced ACQ phenomenon commonly observed in traditional PSs, thereby enhancing their antitumor efficacy[26].

Figure 4 Aggregation-induced emission luminogens treatment of tumor processes by photodynamic therapy and cancer cell damage triggered by generation of reactive oxygen species. A: The process and principle of photodynamic therapy for tumor treatment; B: Aggregation-induced emission photosensitizers accumulate in tumor cells and generate reactive oxygen species to kill tumor cells after illumination. AIEgens: Aggregation-induced emission luminogens; PSs: Photosensitizers; ROS: Reactive oxygen species. Created in Figdraw.

The ROS generated by AIE PSs upon light irradiation can damage mitochondria and nuclear DNA, thereby triggering apoptosis, pyroptosis, and immunogenic cell death (ICD) of tumor cells, among other effects[27]. PDT based on AIE PSs primarily treats tumors by inducing ICD to stimulate antitumor immunotherapy[28]. Under light irradiation, AIE PSs generate ROS, which subsequently activate damage-associated molecular patterns. These include calreticulin, high-mobility group box 1 protein secreted by tumor cells, and heat shock protein 70. This process further promotes dendritic cell maturation and T cell activation, enhancing the anti-tumor immune response. Additionally, AIE PS-based PDT can target tumors by modulating the tumor immune microenvironment. For example, it can improve physical barriers, such as reducing cancer-associated fibroblasts, and chemical barriers, such as regulating acidic and hypoxic metabolic conditions[28]. Additionally, AIEgens can specifically target cancer cells through surface modifications (such as linking antibodies, peptides, or ligands), reducing damage to normal cells. AIEgens can also serve as drug carriers, precisely delivering anticancer drugs (e.g., doxorubicin, paclitaxel) to tumor sites. The combination of AIEgens with multiple therapies using AIE PSs further enhances the therapeutic efficacy of PDT[24,29].

Recently, AIE PS-based PDT has demonstrated significant efficacy against GI tumors. Moreover, combining AIE PSs with other therapies has opened new avenues for clinical research.

Oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck tumor, and it has a high mortality rate[30]. Due to its complex anatomical structure and proximity to key structures such as major blood vessels, nerves, and the pharynx, OSCC presents significant challenges in clinical treatment[31]. Therefore, exploring image-guided surgery or innovative non-invasive therapies is crucial to prolong survival and preserve the patient's appearance and function[32].

AIEgens have shown promise in effectively imaging and treating OSCC. A theranostic agent known as Methoxy-naphthyl-functionalized triphenylamine-thiophene-benzo[1,2-c:4,5-c′]bis([1,2,5]thiadiazole) NPs (BTB NPs) has AIE characteristics, as it enables visualization of tumors located in the oral cavity and the base of the tongue, thereby assisting clinicians in performing more precise tumor removal[33]. Meanwhile, BTB NPs-mediated photothermal therapy (PTT) can selectively induce local heating in the tongue tumor tissue without affecting normal tongue function, providing a non-invasive/minimally invasive treatment method[33]. In addition, Zhang et al[34] synthesized an AIEgen by encapsulating N-Methyl diphenylamine-methylthiophene-benzo[1,2-c:4,5-c′]bis([1,2,5]thiadiazole) (NMB) in azo-containing polymers (NMB@NPs). This AIEgen showed significant PTT effects and high tumor inhibition rates in a patient-derived xenograft (PDX) model[34], demonstrating the potential of AIEgens in the clinical treatment of OSCC. Furthermore, PDT based on AIE PSs can effectively treat OSCC. A novel AIE PS has been designed for clinical laser treatment of oral tumors[35]. It uses methoxy-substituted triphenylamine as the electron donor, fumaronitrile as the auxiliary acceptor, and 2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran as the acceptor, and was named AIEPS5. By connecting a PEG chain with a terminal azide group to AIEPS5, it self-assembled into AIEPS5-NPs. The anti-Her-2 nanobody was then modified on the NP surface, ultimately yielding AIEPS5-NPs-NB. AIEPS5-NPs-NB was used to treat the OSCC PDX mouse model. The experimental results demonstrated that AIEPS5-NPs-NB effectively ablated tumors under laser irradiation[35]. Because human epidermal growth factor receptor 2 (Her-2) is highly positively expressed in gingival cancer tissues, the construction of an AIE PS nanoplatform conjugated with anti-Her-2 nanobodies improved AIEPS5 targeting to oral tumors. The results showed that this material can perform precise personalized PDT for OSCC and has potential in the clinical treatment of OSCC[35].

Studies have shown that the combination of PDT based on AIEgens and immune checkpoint blockade (ICB) can significantly enhance the antitumor effect[36-39]. The phototheranostic NPs Triphenylamine-thiophene-3-(dicyanomethylene)-2,3-dihydrobenzo[b]thiophene-1,1-dioxide NPs (TSD NPs) can be used for photoimmunotherapy and ICB immunotherapy against OSCC[40]. The results showed that TSD NPs under near-infrared (NIR) laser irradiation can upregulate the PD-L1 expression in cancer cells, making them suitable for combination with αPD-L1 ICB immunotherapy. Further studies showed that the combination of TSD NPs and αPD-L1 can completely eradicate solid OSCC tumors without adverse side effects on normal tissues[40], indicating that the combination of PDT based on AIEgens and ICB can effectively treat OSCC.

AIEgens have shown excellent potential in the treatment of oral cancer. They can selectively induce localized heating of tongue tumor tissue via PTT and have demonstrated significant tumor suppression in a PDX model. AIEgens can also effectively treat OSCC through PDT, with targeting improved by conjugation to the gingival cancer-specific marker Her-2. Furthermore, combining PDT with ICB significantly enhances therapeutic efficacy against OSCC.

EC

EC is the 11th most common cancer and the sixth leading cause of cancer-related death worldwide. It is usually diagnosed at an advanced stage, making it nearly impossible to extend life expectancy beyond a few months[41]. Therefore, early diagnosis and treatment of EC are extremely important. Lu et al[42,43] designed and synthesized a series of amphiphilic copolymers containing AIEgens. Confocal fluorescence images showed that these amphiphilic copolymers can be endocytosed by the human esophageal precancerous CP-A cell line and distributed in the cytoplasm, emitting obvious fluorescence[42,43]. This study indicates that AIEgens can identify esophageal cancer cells. Although the application of AIEgens in EC is still limited, this research demonstrates the potential of AIEgens in EC imaging.

GC

GC is a major global health challenge, ranking fifth in global cancer incidence and fourth in cancer mortality[44]. The 5-year survival rate for advanced-stage patients is less than 10%[45]. Therefore, early diagnosis and effective treatment of GC are crucial, and AIEgens have shown significant advances in GC detection and treatment.

AIEgens hold promise for the clinical detection of GC. For instance, when combined with suspension array technology, AIEgens overcome the ACQ effect typically seen with high concentrations of fluorescent groups in conventional suspension array technology. This innovation enables the simultaneous quantitative detection of GC-related miRNAs and allows for the multiplexed detection of plasma biomarkers associated with GC[46]. Additionally, Ouyang et al[47] synthesized an AIE-NP drug delivery system based on mesenchymal stem cells (MSC). In this system, TPE is loaded onto the copolymer polyethylenimine-poly (ε-caprolactone), combined with paclitaxel, and modified with a cell-penetrating peptide to enhance nanoparticle uptake. The study demonstrated that MSCs serve as an ideal drug carrier, improving the bioavailability of anticancer drugs[48], enhancing the targeting of AIE-NPs to GC, and enabling real-time monitoring of drug distribution and GC detection[47].

PDT utilizing AIE PSs has shown significant efficacy in the treatment of GC. One example is TPE-substituted pyridinium salt (TPE-Py), an AIE PS capable of inducing apoptosis in GC cells. Experimental results demonstrated that combining TPE-Py with the anticancer drug paclitaxel further improved the therapeutic effect against GC[49]. Moreover, research by Zhang et al[50] revealed that TPE-Py selectively targets mitochondria, where it severely impairs mitochondrial function, disrupts the redox balance and promotes ROS generation, enhancing its apoptotic mechanism in GC cells[50]. In addition, Zhu et al[51] developed a type I AIE PS system in which AIEgens and proton pump inhibitors (PPIs) were co-loaded into exosomes. PPIs influence glutamine metabolism, further reducing glutathione-mediated resistance to ROS[52], while tumor-derived exosomes enhance targeting and delivery efficiency to GC cells[53]. In a MGC803 GC subcutaneous model, this AIE PS system achieved a high tumor growth inhibition rate and even promoted tumor immunogenic death, demonstrating a significant PDT effect[51]. Furthermore, a gold nanoprism system integrated with AIEgens has been successfully fabricated and characterized[54]. These gold nanoprisms not only serve as efficient drug carriers but also enhance tumor targeting[55]. The study showed that dual-targeted gold nanoprisms could effectively perform PTT against SGC-7901 human GC cells in vitro[54].

The integration of AIEgens into suspension array technology enables the simultaneous detection of multiple plasma biomarkers for GC. Additionally, the combination of AIEgens with MSCs enhances the targeting of GC, giving AIEgens a significant advantage in GC detection. Meanwhile, AIEgens can improve GC targeting when combined with anticancer drugs such as paclitaxel, PPIs, and gold nanoprisms, together enhancing the therapeutic efficacy of PDT and PTT.

CRC

CRC is the third most common cancer and the fourth leading cause of cancer-related death globally. Hence, the early diagnosis and treatment of CRC are of great importance[56]. AIEgens have made significant advancements in the identification, imaging, and treatment of CRC.

AIEgens can effectively identify and target colorectal tumor cells. For instance, a novel AIE fluorescent probe, named probe 3, was developed to identify CRC tissues by tracking the nuclei of cancer cells in adjacent tissues, providing valuable guidance for precise CRC surgery[57]. The development of specific probes based on AIE technology has enhanced the accumulation of AIEgens at colorectal tumor sites. Feng et al[58] synthesized and screened TPE-OM, which introduces electron-donating n-pentyloxy groups at the para positions of two phenyl rings of TPE. TPE-OM targets mitochondria in tumor cells through electrostatic attraction between its positively charged pyridine groups and the negative transmembrane potential of mitochondria[59]. Their research demonstrated that PDT based on TPE-OM inhibited the expression of genes promoting the CRC cell cycle, effectively inducing cancer cell death[58].

Another important marker in tumor progression is pyruvate kinase isozyme type M2 (PKM2)[60]. Based on this, an AIE probe named TEPC466 was designed, incorporating the fluorescent agent coumarin into the PKM2 activator TEPP-46. TEPC466 specifically targets PKM2 proteins in CRC cells, improving probe accumulation at the tumor site[60].

Additionally, Shi et al[61] developed a cyclic arginine-glycine-aspartic acid tripeptide (cRGD)-conjugated probe with AIE properties, making it the first fluorescent probe capable of detecting endogenous human integrin receptors in living cells. Since integrin αvβ3 plays a critical role in tumor growth and metastasis, and serves as a unique molecular target for early detection and treatment of aggressive solid tumors, this probe is highly significant. Experimental results confirmed that the cRGD-conjugated probe exhibited significantly enhanced enrichment in CRC tumors[61].

AIE PS-based PDT can effectively treat CRC. For example, a platelet-like MnO₂ nanozyme/AIEgen composite material (PMD) coated with platelet membranes enabled better and more specific targeting of the tumor site for transportation[62,63]. Furthermore, Zhu et al[64] designed and developed a new AIEgen-based hybrid system (AE). Leveraging the the hypoxia-tumor tissue tropism of Escherichia coli (E. coli)[65], AE can efficiently target colorectal tumors. At the same time, they overcame the limitation of poor light penetration in deep tissues during PDT by combining the treatment with interventional devices, ultimately achieving effective treatment of orthotopic CRC in mice and enhancing the overall PDT effect[63,64]. In addition, a NIR-II AIE PS, Diphenylamine-thiophene-2-methylthiophene-vinylene-benzo[c,d]indolium NPs (DTTVBI NPs), exhibits selective photosensitivity at tumor sites while self-inactivating in normal tissues, effectively eliminating patient-derived CRC tumor xenografts[7]. These results suggest that PDT based on DTTVBI NPs holds strong potential for clinical application in treating CRC.

By designing specific probes, AIEgens can efficiently target CRC tumors and enhance their accumulation at the lesion site. For example, AIE probes targeting CRC markers such as PKM2 and cRGD peptides significantly enhance their accumulation at tumor sites, thereby improving the efficiency of CRC detection. In addition, in AIEgen-based PDT, the attachment of AIEgens to platelet membranes and E. coli enhances delivery efficiency, while the use of interventional devices helps overcome the limitation of light penetration depth, significantly improving the therapeutic efficacy of CRC. Finally, NIR region II AIE PSs exert photosensitization at the tumor site and self-deactivate in normal tissues, providing a new strategy for the clinical treatment of CRC.

In conclusion, AIEgens have played a significant role in the imaging, diagnosis, and treatment of GI diseases. As shown in Table 1, we summarize the distinct advantages of AIEgens in various GI tumors. In addition, combining AIEgens with multiple therapeutic strategies has enhanced the accumulation and therapeutic efficacy of AIE materials at GI tumor sites. In Figure 5, we summarize the combined treatment methods of AIE materials in GI tumor therapy.

Figure 5 Combination of aggregation-induced emission luminogens with multiple therapies to improve the effectiveness of aggregation-induced emission luminogens in gastrointestinal diseases. AIEgens: Aggregation-induced emission luminogens; TPE: Tetraphenylethylene; GC: Gastric carcinoma; CRC: Colorectal cancer; E. coli: Escherichia coli; OSCC: Oral squamous cell carcinoma. The compound structures were drawn using KingDraw.

Table 1 Aggregation-induced emission luminogens show unique benefits in different gastrointestinal tumors.

Tumor type	Advantages of AIEgens
OSCC	Avoids other critical areas in the mouth and precisely targets the tumor site for more efficient imaging, diagnosis and treatment
EC	Currently unavailable
GC	Multiplexed assays for plasma markers of gastric cancer, high-contrast imaging, high-sensitivity detection, and synergistic treatment with PDT and PTT
CRC	AIEgens can clearly display tumor boundaries and tiny lesions to assist in early diagnosis, provide dynamic information through real-time imaging

AIEgens: Aggregation-induced emission luminogens; OSCC: Oral squamous cell carcinoma; GC: Gastric carcinoma; CRC: Colorectal cancer; PDT: Photodynamic therapy; PTT: Photothermal therapy.

LIMITATIONS AND PROSPECTS OF AIEGENS

AIEgens show promising application prospects in fields such as GI disease diagnosis and treatment. However, their application in this area still faces several challenges.

AIEgen-based imaging and typically require light activation, but the limited penetration depth of lasers makes it difficult to reach diseased areas within the GI tract[66]. To address this issue, researchers are developing AIEgens that can be activated by NIR light sources, which have deeper tissue penetration[23]. Additionally, integrating endoscopic techniques to directly guide light to the target area can enhance the precision of illumination. Furthermore, designing AIEgens with higher sensitivity and specificity, as well as developing targeted delivery systems, can reduce reliance on light penetration depth. By optimizing the molecular structure of AIEgens, designing nanocarriers for targeted delivery, and combining them with other therapeutic approaches, their sensitivity and specificity can be significantly improved.

The use of AIE PSs in PDT for GI diseases also presents clinical challenges. After injection into the body, AIE PSs may circulate systemically, potentially resulting in residual accumulation in normal tissues or cells. When exposed to sunlight, these residual materials can continue to generate ROS, potentially damaging healthy cells[67]. Therefore, a key challenge in PDT is ensuring rapid AIE PS clearance or deactivation after treatment. To address this, it is essential to thoroughly study the metabolic pathways of AIE PSs and conduct long-term in vivo toxicity assessments before clinical application. Additionally, developing AIE PSs with rapid metabolic clearance or self-deactivation properties could enable their quick excretion or loss of photosensitive activity post-treatment, thereby minimizing residual effects.

Although AIEgens show great potential in treating GI diseases, challenges remain, including limited light penetration depth, insufficient sensitivity and specificity, and residual post-treatment effects. Interdisciplinary collaboration across materials science, nanotechnology, PDT, and clinical medicine can address these issues, advancing the broader application of AIEgens in GI disease treatment.

CONCLUSION

In recent years, the application of AIEgens in GI diseases has experienced rapid advancements, presenting novel approaches for imaging, diagnosing, and treating GI pathogens, IBD, and GI cancers. In contrast to traditional imaging modalities, AIEgen-based imaging exhibits superior luminescence efficiency and accuracy, thereby facilitating surgical guidance. Furthermore, AIEgens can be combined with targeted probes, thereby enhancing the specificity during GI disease diagnosis. The development of PSs with AIE characteristics has shown promising efficacy in PDT for treating GI tumors. The combination of AIE PSs with other treatment strategies has also given rise to new research directions in clinical treatment. Accordingly, with the continuous evolution and enhancement of technology, it is anticipated that AIEgens will assume an increasingly pivotal role in enhancing imaging capabilities as well as diagnostic and therapeutic interventions related to GI diseases.