Yuan Zhang,1,2,* Meixian Liu,1,2,* Shuyun Xue,1,2 Na Li,1,2 Jinjia Hong,1,2 Jiawen Gu,1,2 Xiaoyan Ren,1,2 Huifei Li,1,2 Jie Xu,1,2 Chengxi Zhang,1,2 Tianqi Liang,1,2 Bin Zhao,1,2 Xing Wang1,2 

1Department of Oral and Maxillofacial Surgery, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, People’s Republic of China; 2Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan, 030001, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xing Wang, Shanxi Medical University School and Hospital of Stomatology, Xinjian South Road 63#, Taiyuan, 030001, People’s Republic of China, Email kqwx100@163.com Bin Zhao, Email sxmu0688@126.com

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 (NV-PCN), a novel metal-free and O2-independent photosensitizer designed for PDT. NV-PCN targets Cal-27–induced OSCC by reducing highly expressed H2O2 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 NV not only further improves the cell accessibility of PCN by increasing the content of –NH2 but also provides more reactive sites for H2O2 reduction and facilitates carrier separation. Under illumination, NV-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, NV-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 O2-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.

Keywords: photodynamic therapy, nitrogen vacancy, polymeric carbon nitride, DNA-damage repair, hydroxyl radical