Bioinspired engineering of simplified Type I photosensitizers against hypoxic oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) ranks among the most common malignant neoplasms affecting the oral cavity. Conventional treatments like surgery and chemotherapy often cause severe side effects and a poor prognosis. Photodynamic therapy (PDT), characterized by its non-invasive nature, high specificity, and minimal invasiveness, has shown promise as an alternative therapeutic approach. The fundamental principle underlying PDT is a photochemical reaction: photosensitizers (PSs) are activated by light at specific wavelengths to generate reactive oxygen species (ROS), ultimately resulting in cancer cell death. However, the clinical translation of PDT for OSCC is hindered by two critical challenges: most conventional PSs rely on complex synthetic routes, leading to high synthesis costs and low yields; additionally, traditional Type II PSs are highly susceptible to the hypoxic OSCC microenvironment, compromising therapeutic efficacy. The D-π-A molecular engineering strategy is a common approach in developing new PSs, where π-bridges are often constructed using various synthetic heterocycles that further increase synthetic complexity. To address these dual challenges, we introduced natural purine (a readily available, structurally simple heterocycle) as the π-bridge in the D-π-A framework and modified its C8 position with various electron-withdrawing acceptors via straightforward synthetic steps, leading to the development of an efficient PS ( PCP ) that operates via a Type I mechanism. PCP exhibited remarkable efficacy in the photodynamic ablation of tumor tissues and potently suppressed OSCC proliferation in both in vitro and in vivo settings, while also demonstrating favorable biocompatibility. The strategy of employing natural heterocycles (purine) simplifies the synthesis of high-performance PSs and establishes a promising foundation for advancing PDT in OSCC therapy, overcoming the key bottlenecks of conventional PSs. • Novel photosensitizers based on purine skeletons simplify photosensitizer fabrication remarkably • PCP exhibits potent Type I ROS generation. • PCP -mediated photodynamic therapy effectively ablated OSCC tumor tissue and inhibited tumor growth.