Photosynthetic Plant-Derived Nanovesicles Precisely Amplify Photodynamic Effect by Light-Activated Oxygen Generation for Enhanced Cancer Photoimmunotherapy.

Abstract

Photodynamic immunotherapy has emerged as a promising cancer therapeutic strategy, yet its efficacy is crucially hindered by the hypoxic and immunosuppressive tumor microenvironment (TME). Herein, we present a bioinspired nanoplatform that leverages the natural photosynthetic capabilities of spinach-derived nanovesicles (SDNV) for light-excited oxygen evolution to address this critical challenge. SDNV is engineered to encapsulate aggregation-induced emission luminogens (AIEgen), forming AIE@SDNV nanoparticles with excellent biocompatibility and transmembrane permeability. Upon irradiation, SDNV generates substantial oxygen as a substance for AIEgen to produce reactive oxygen species, thus improving the photodynamic efficacy by triggering severe cellular lipid peroxidation and calcium ion imbalance. This leads to potent tumor cell destruction and immunogenic cell death. Subsequently, significant release of damage-associated molecular patterns from tumor cells enhances systemic antitumor immunity via the cGAS-STING signaling pathway and activates immune responses within the TME. Moreover, SDNV enables precise AIEgen delivery and prolonged tumor retention. Simultaneously, AIE@SDNV-mediated photoimmunotherapy effectively suppresses both primary and distant tumors in a bilateral tumor model. This study provides a promising strategy for efficiently delivering a therapeutic agent, improving hypoxia-restricted photodynamic therapy, and reversing the immunosuppressive TME, thereby achieving potentiated antitumor efficacy and highlighting the potential of plant-derived nanovesicles in advancing cancer nanomedicine.