Photodynamic therapy (PDT) is a promising cancer treatment method, but its efficacy is often impaired due to tumor hypoxia and limited immune activation. We have developed a multifunctional photosynthesis nanoplatform (PnanoCB), derived from the microcystis vesiculosa bacterium, aiming to alleviate hypoxia, enhance ROS-mediated tumor cell killing, and activate anti-tumor immunity. The cyanobacteria are restructured into vesicles derived from protoplasts, retaining photosynthetic capabilities and chlorophyll, and through a pH-sensitive pH low insertion peptide (pHLIP) linker, they are connected to a matrix metalloproteinase-2 (MMP-2) that can be cleaved for anti-PD-L1 peptides, used for tumor-targeted immune checkpoint blockade. After red light irradiation, PnanoCB efficiently generates oxygen in situ, overcoming hypoxia and significantly enhancing ROS production induced by PDT. Combining PnanoCB with a fasting mimetic diet (FMD) further improves tumor accumulation and therapeutic efficacy. The combination of PnanoCB, light irradiation, and foot-and-mouth disease achieved the strongest tumor suppression in the 4T1 breast cancer model and effectively prevented tumor recurrence in re-challenge models, with no significant toxicity to major organs. Overall, PnanoCB significantly alleviates hypoxia, promotes immunogenic cell death, and activates a robust dendritic cell (DC) maturation by stimulating the interferon gene (STING) pathway. This study demonstrates a strategy combining photosynthesis oxygen generation, photodynamic immunotherapy, and metabolic intervention to reshape the tumor microenvironment and induce robust systemic anti-tumor immunity. This research was published in Advanced Materials under the title "Photosynthetic Nanobacteria Drive Metabolic-Impaired Synergy for Hypoxia-Resistant Cancer Therapy".
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DOI: 10.1002/adma.72834