Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510055, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510080, PR China.
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou, 510006, PR China.
Biomaterials. 2022 Oct;289:121757. doi: 10.1016/j.biomaterials.2022.121757. Epub 2022 Aug 24.
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, TiO@Ru@siRNA is constructed from a ruthenium-based photosensitizer (Ru) modified-TiO nanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiO@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, TiO@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 TiO@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.
缺氧和免疫微环境的改变与口腔鳞状细胞癌（OSCC）的治疗效果和预后密切相关。在此，构建了一种由钌基光敏剂（Ru）修饰的负载缺氧诱导因子-1α（HIF-1α）siRNA 的 TiO 纳米颗粒（NPs）组成的新型纳米复合材料 TiO@Ru@siRNA。在可见光照射下，TiO@Ru@siRNA 可以引发 I 型和 II 型光动力效应，有效地导致溶酶体损伤、HIF-1α 基因沉默和 OSCC 细胞消除。由于缺氧缓解和细胞焦亡诱导，TiO@Ru@siRNA 通过下调关键免疫抑制因子、上调免疫细胞因子和激活 CD4 和 CD8 T 淋巴细胞来重塑免疫微环境。此外，患者来源的异种移植（PDX）和大鼠口腔实验性致癌模型证明，TiO@Ru@siRNA 介导的光动力疗法显著抑制肿瘤生长和进展，并显著增强癌症免疫。总之，这项研究提出了一种有效的缺氧适应光免疫治疗纳米系统，具有预防和治疗 OSCC 的巨大潜力。
