Stepwise mitochondria‐targeted photodynamic immunotherapy enabled by an outer membrane vesicles‐based nanoplatform for synergistic tumor ablation and immune reprogramming

Abstract Photodynamic immunotherapy (PDIT) integrates reactive oxygen species (ROS)‐mediated tumor destruction with immune activation. However, its effectiveness is often hindered by tumor hypoxia, poor tumor‐targeted delivery, and the immunosuppressive microenvironment. Here, we introduce BDPM@OMVs , a biomimetic nanoplatform designed to overcome these challenges. This system uses bacterial outer membrane vesicles to encapsulate a novel, heavy‐atom‐free aggregation‐induced emission photosensitizer ( BDPM ). Our platform enables stepwise lysosome‐to‐mitochondria trafficking for enhanced PDIT. BDPM@OMVs exhibits strong near‐infrared absorption and efficient intersystem crossing, leading to both Type I and Type II ROS generation, which sustains photodynamic performance even under hypoxic conditions. Upon light irradiation, BDPM@OMVs trigger photochemical internalization (PCI), disrupting lysosomes and releasing BDPM into the cytosol. The freed BDPM then selectively accumulates in mitochondria, where continues light exposure generates robust ROS, causing mitochondrial dysfunction and activating apoptosis. This process effectively amplifies tumor cell eradication. Simultaneously, BDPM@OMVs reprogram the tumor immune microenvironment by promoting macrophage repolarization from the immunosuppressive M2 to the pro‐inflammatory M1 phenotype, as evidenced by upregulated TNF‐α, IL‐1β, and CD86 expression. In vivo studies confirm that BDPM@OMVs achieve efficient tumor accumulation, allow for real‐time NIR imaging, and provide superior therapeutic outcomes. This work presents a versatile and hypoxia‐resilient PDIT strategy that synergistically integrates precise subcellular photodamage with immune modulation to overcome resistance in solid tumors.