The Novel Hydrogen-PT2385-silncARSR Nanocomplex Impairs Tumor Angiogenesis and Mitochondrial Activity in Sunitinib-Resistant Renal Cancer

Hydrogen therapy has emerged as a promising agent for cancer treatment. Earlier research demonstrated that hydrogen (H 2 ) possesses anti-angiogenic effects across multiple tumor types. However, no studies have yet investigated the anti-angiogenic effects of H 2 in sunitinib-resistant clear cell renal cell carcinoma (ccRCC) or elucidated the mechanism involved. Besides, both Hypoxia-inducible factor 2α (HIF-2α) and lncRNA Activated in RCC with sunitinib resistance (lncARSR) play essential roles in mediating ccRCC sunitinib resistance. Nevertheless, traditional multidrug combination strategy fails to achieve precise and effective suppression of drug-resistance related targets in conjunction with gas therapy. Therefore, we engineered a tumor-targeted nanocomplex, enabling localized H 2 generation and efficient PT2385 and small interfering RNA targeting lncARSR (silncARSR) delivery to inhibit HIF-2α and downregulate lncARSR in sunitinib-resistant ccRCC. Mechanistically, in situ generated hydrogen and lncARSR knockdown effectively suppresses tumor angiogenesis by downregulating vascular endothelial growth factor A(VEGFA) secretion from sunitinib-resistant cancer cells and M2-like tumor-associated macrophages (TAMs). Thus, the anti-angiogenic activity of PT2385 (HIF-2α inhibitor) was potentiated by H 2 and silncARSR significantly. Moreover, the combination of H 2 , silncARSR and PT2385 exerts significantly potentiated efficacy in modulating apoptosis-related protein expression and ultimately enhancing cancer cell mitochondrial apoptosis. The demonstrated high therapeutic efficacy and great biocompatibility of this Hydrogen-PT2385-silncARSR nanocomplex underscore the clinical translation potential for overcoming ccRCC sunitinib resistance.