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

Pyroptosis is a unique programmed cell death pattern, and targeting it is an effective strategy against cancer therapy by overcoming apoptosis resistance. However, Golgi apparatus-targeted aggregation induced emission (AIE) photosensitizer as pyroptosis inducer for efficient antitumor treatment has not been reported. In this study, we successfully synthesized three new AIEgens, including TMN, TBN and TCN, by changing functional groups through a reasonable molecular design strategy, which targeted mitochondria, lysosome and Golgi apparatus (GA), respectively. In vitro experiments demonstrated that TCN exhibited the strongest reactive oxygen species (ROS) production ability and significant phototoxicity. Therefore, TCN as the GA-targeted AIE photosensitizer wore biomimetic hybrid extracellular vesicles (EVs) and M1-type macrophage membranes (denoted as EM@TCN) as pyroptosis inducer were rationally designed and engineered to trigger the production of GA cytotoxic ROS in situ . EM@TCN plus white light irradiation caused GA oxidative stress and induced pyroptosis synergistic photoimmunotherapeutic, which could rebuild tumor microenvironment and improve tumor immunogenicity. Combined with α PD-L1 (anti-mouse PD-L1 antibody), the biomimetic hybrid delivery system EM@TCN significantly inhibit the both primary and distant tumors, and effectively suppress the orthotopic breast tumor. This is the first report on a hybrid nanovesicle coated GA-targeted AIE photosensitizer to induce pyroptosis for combination with α PD-L1 to enhance antitumor photoimmunotherapy.