Boosting Hydroxyl Radical Generation with Nitrogen Vacancy-Modified Carbon Nitride for Triggering Dual Damage of Cancer Nucleus DNA-Mitochondria against Hypoxic Tumors.

INTRODUCTION: Oral squamous cell carcinoma (OSCC) is a prevalent and deadly cancer, with over 350,000 new cases yearly. A hypoxic tumor microenvironment is the bottleneck of photodynamic therapy (PDT) and significantly weakens overall therapeutic efficacy. METHODS: In this study, we introduce nitrogen vacancy-modified PCN (N(V)-PCN), a novel metal-free and O(2)-independent photosensitizer designed for PDT. N(V)-PCN targets Cal-27-induced OSCC by reducing highly expressed H(2)O(2) in tumors to highly reactive •OH. This innovative approach aims to overcome the limitations posed by the hypoxic environment and enhance the effectiveness of PDT in treating OSCC. RESULTS: The introduction of N(V) not only further improves the cell accessibility of PCN by increasing the content of -NH(2) but also provides more reactive sites for H(2)O(2) reduction and facilitates carrier separation. Under illumination, N(V)-PCN generates a burst of •OH around the nuclei and mitochondria of Cal-27 cells, which effectively kills the cells via synchronously leading to DNA damage and mitochondrial dysfunction. Compared to the conventional photosensitizer chlorin e6, N(V)-PCN-based PDT exhibits excellent anticancer performance in vitro and in vivo, highlighting its potential as a next-generation therapeutic agent. CONCLUSION: Collectively, the high •OH-generation efficiency, strong anticancer activity, and overall safety of the O(2)-independent nanoparticle opens up new avenues for in-depth study on carbon nitride-based cancer PDT strategies. This work offers new hope for the effective treatment of OSCC and other challenging cancers.