This study presents, for the first time, a hybrid nanoplatform camouflaged with extracellular vesicles and M1 macrophage membranes, enabling targeted delivery of an AIE photosensitizer to the Golgi apparatus. This approach effectively induces tumor cell pyroptosis and activates immunogenic cell death, significantly enhancing the efficacy of antitumor photoimmunotherapy.
Literature Overview
The article titled 'Extracellular vesicles-derived hybrid biomimetic nanoplatforms camouflaged Golgi apparatus-targeted aggregation induced emission photosensitizer to elicit pyroptosis and immunogenic cell death for efficient antitumor photoimmunotherapy,' published in Acta Pharmaceutica Sinica B, reviews and summarizes a novel strategy involving the design of a new aggregation-induced emission (AIE) photosensitizer, TCN. This agent specifically targets the Golgi apparatus and is delivered via a biomimetic nanocarrier, EM@TCN. Under white light irradiation, it efficiently induces tumor cell pyroptosis and immunogenic cell death, thereby activating systemic antitumor immune responses. This approach significantly suppresses both primary and distant tumor growth, with further enhanced efficacy when combined with αPD-L1 antibody therapy. The study offers new insights into overcoming fluorescence quenching in traditional photodynamic therapy and improving tumor immunogenicity.Background Knowledge
Pyroptosis is a form of programmed cell death mediated by the gasdermin protein family, characterized by plasma membrane pore formation, cell swelling, rupture, and the release of large amounts of pro-inflammatory cytokines, triggering robust antitumor immune responses. Unlike apoptosis, pyroptosis effectively overcomes tumor resistance to apoptotic pathways and, through the release of damage-associated molecular patterns (DAMPs) and cytokines such as IL-1β and IL-18, promotes dendritic cell maturation and T-cell infiltration, transforming 'cold' tumors into 'hot' tumor microenvironments. Thus, inducing pyroptosis has become a promising strategy in cancer immunotherapy.
Photodynamic therapy (PDT) utilizes photosensitizers that generate reactive oxygen species (ROS) upon exposure to specific wavelengths of light, enabling selective killing of cancer cells. However, conventional photosensitizers often suffer from aggregation-caused quenching (ACQ), limiting their imaging and therapeutic efficiency. In contrast, aggregation-induced emission (AIE) photosensitizers exhibit enhanced fluorescence and efficient ROS generation in the aggregated state, overcoming ACQ and making them ideal candidates for PDT. Subcellular organelle targeting is key to enhancing PDT efficacy. The Golgi apparatus, due to its central role in protein modification and trafficking, and its susceptibility to oxidative stress-induced cytotoxicity, has emerged as a promising target. Yet, highly efficient and specific AIE photosensitizer systems for Golgi targeting remain lacking.
Moreover, the biocompatibility, targeting ability, and immune evasion capacity of nanocarriers directly affect drug delivery efficiency. Extracellular vesicles (EVs) offer natural low immunogenicity, long circulation time, and excellent biocompatibility, while M1 macrophage membranes possess tumor-tropic properties and the ability to reprogram the immune microenvironment. Constructing a hybrid carrier from EVs and M1 membranes holds promise for achieving synergistic targeting and immune modulation, thereby enhancing therapeutic outcomes. This study, therefore, proposes a novel biomimetic hybrid nanoplatform for targeted delivery of Golgi-specific AIE photosensitizers to induce pyroptosis and immunogenic cell death, enabling efficient photoimmunotherapy.
Research Methods and Experiments
The researchers designed and synthesized three AIE luminogens with a D—π—A structure—TMN, TBN, and TCN—targeting mitochondria, lysosomes, and the Golgi apparatus, respectively. Their subcellular localization and ROS generation efficiency were evaluated through photophysical characterization, confocal microscopy, and cellular uptake assays. Results showed that TCN exhibited the strongest type II ROS generation capability, excellent photostability, and specific targeting to the Golgi apparatus.
To enhance the in vivo delivery efficiency of TCN, a hybrid nanocarrier, EM@TCN, was constructed by fusing extracellular vesicles (EVs) derived from 4T1 breast cancer cells with M1 macrophage membranes (MM). Its physical properties and membrane protein retention were validated using dynamic light scattering (DLS), transmission electron microscopy (TEM), and Western blotting. In vitro experiments assessed cellular uptake pathways, cytotoxicity, ROS generation, and effects on tumor cell migration and invasion.
Western blotting, LDH, ATP, IL-1β, and IL-18 assays were used to verify pyroptosis-related protein expression and inflammatory cytokine release. Flow cytometry was employed to analyze CRT exposure and HMGB1 release as markers of immunogenic cell death (ICD). RNA-seq analysis revealed functional enrichment pathways of differentially expressed genes following EM@TCN treatment. In a 4T1 tumor-bearing mouse model, the in vivo biodistribution, antitumor efficacy, and combination effect with αPD-L1 were evaluated, along with immune cell infiltration and systemic immune responses.Key Conclusions and Perspectives
Research Significance and Prospects
This study represents the first successful application of a Golgi apparatus-targeted AIE photosensitizer in pyroptosis induction and photoimmunotherapy, expanding the potential of AIE materials in subcellular organelle-targeted therapies. Through rational molecular design, the specifically targeted photosensitizer TCN overcomes the lack of subcellular selectivity in conventional photosensitizers, enhancing the precision and efficacy of PDT.
The EM@TCN hybrid nanoplatform integrates the biocompatibility of EVs with the immunomodulatory functions of M1 membranes, achieving dual advantages of efficient targeted delivery and tumor microenvironment reprogramming. This system not only directly kills tumor cells but also activates systemic immune responses by inducing pyroptosis and ICD, breaking immune tolerance. It offers a new strategy to overcome the limited efficacy of PD-1/PD-L1 monotherapy.
Future studies may explore the platform’s applicability in other solid tumor models, optimize light irradiation parameters for deep-tissue treatment, and evaluate long-term immune memory effects. Additionally, this platform provides a valuable reference for the design of other subcellular organelle-targeted drug delivery systems, holding broad translational potential.
Conclusion
This study developed a biomimetic hybrid nanoplatform, EM@TCN, based on the fusion of extracellular vesicles and M1 macrophage membranes, designed to deliver a novel Golgi apparatus-targeted AIE photosensitizer, TCN. Upon white light irradiation, the system efficiently generates reactive oxygen species, triggering Golgi oxidative stress, activating gasdermin-mediated pyroptosis, and inducing immunogenic cell death. Both in vitro and in vivo experiments demonstrated that EM@TCN not only significantly suppresses tumor cell viability and migration but also promotes dendritic cell maturation, enhances T-cell infiltration, and remodels the immunosuppressive microenvironment. When combined with αPD-L1 therapy, it further amplifies antitumor immune responses, effectively controlling both primary and metastatic tumor growth. This work not only pioneers the use of Golgi-targeted AIE photosensitizers in pyroptosis induction but also provides an innovative strategy for developing highly effective photoimmunotherapies, offering significant scientific value and clinical translation potential.
