Photosynthetic chlorella-violet phosphorus nanosheet biohybrid alleviating tumor hypoxia for synergistic...

Tumor metabolic reprogramming, typified by the Warburg effect, promotes hypoxia and immunosuppression in the tumor microenvironment (TME), thereby limiting therapeutic efficacy. Herein, we report a photosynthetic Chlorella (Chl)-violet phosphorus nanosheets (VP) biohybrid system (Chl@VP) for synergistic O₂ supply, metabolic perturbation, and photodynamic therapy (PDT)-enhanced tumor treatment. In this system, Chl continuously generates O₂ under irradiation to alleviate hypoxia, while VP produce reactive oxygen species (ROS) and release phosphate species for metabolic modulation. Chl@VP significantly enhances ROS generation, induces mitochondrial damage, elevates intracellular phosphate levels, and reduces lactate production, suggesting disruption of the glycolysis-dominant metabolic state of tumor cells. In vivo, Chl@VP combined with laser irradiation exhibits potent tumor suppression and reduced HIF-1α expression, indicating effective hypoxia relief. Moreover, Chl@VP has been demonstrated to promote dendritic cell maturation, thereby enhancing CD8⁺ T cell activation and tumor penetration, and decreasing regulatory T-cell populations, demonstrating effective immune microenvironment remodeling. Overall, Chl@VP achieves amplified antitumor efficacy through the synergistic integration of hypoxia alleviation, phosphate-mediated metabolic intervention, and ROS-amplified oxidative stress, providing a bioinspired strategy for combining metabolic regulation with PDT for cancer therapy.