Ru(II)-modified TiO2 nanoparticles for hypoxia-adaptive photo-immunotherapy of oral squamous cell carcinoma

Abstract

The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiO₂@Ru@siRNA is constructed from a ruthenium-based photosensitizer (Ru) modified-TiO₂ nanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiO₂@Ru@siRNA can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiO₂@Ru@siRNA reshapes the immune microenvironment by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4⁺ and CD8⁺ T lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiO₂@Ru@siRNA-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment.