Tumor-activated in situ synthesis of single-atom catalysts for O2-independent photodynamic therapy based on water-splitting

Single-atom catalysts (SACs) have attracted interest in photodynamic therapy (PDT), while they are normally limited by the side effects on normal tissues and the interference from the Tumor Microenvironment (TME). Here we show a TME-activated in situ synthesis of SACs for efficient tumor-specific water-based PDT. Upon reduction by upregulated GSH in TME, C₃N₄-Mn SACs are obtained in TME with Mn atomically coordinated into the cavity of C₃N₄ nanosheets. This in situ synthesis overcomes toxicity from random distribution and catalyst release in healthy tissues. Based on the Ligand-to-Metal charge transfer (LMCT) process, C₃N₄-Mn SACs exhibit enhanced absorption in the red-light region. Thereby, a water-splitting process is induced by C₃N₄-Mn SACs under 660 nm irradiation, which initiates the O₂-independent generation of highly toxic hydroxyl radical (·OH) for cancer-specific PDT. Subsequently, the ·OH-initiated lipid peroxidation process is demonstrated to devote effective cancer cell death. The in situ synthesized SACs facilitate the precise cancer-specific conversion of inert H₂O to reactive ·OH, which facilitates efficient cancer therapy in female mice. This strategy achieves efficient and precise cancer therapy, not only avoiding the side effects on normal tissues but also overcoming tumor hypoxia.