siRNA-Loaded Metal-Organic Layers for Targeted Gene Silencing and Radiotherapy Enhancement.

Radiotherapy (RT) remains a cornerstone in cancer treatment; however, its therapeutic efficacy is often limited by tumor fibrosis and radioresistance, primarily driven by transforming growth factor-β (TGF-β) upregulation. To address these challenges, we developed a tris(bipyridyl)ruthenium(II)-based metal-organic layer (RuMOL) for siRNA delivery, designed to simultaneously elicit efficient radiosensitization and silence TGF-β expression, thereby improving tumor response to RT. RuMOL/siRNA demonstrates robust antitumor effects both in vitro and in vivo by reversing fibrosis and potentiating RT-induced DNA damage. Detailed mechanistic studies reveal that TGF-β downregulation effectively suppresses fibrosis, enhances tumor perfusion and oxygenation, and mitigates hypoxia-driven radioresistance, ultimately improving the therapeutic effect of x-ray irradiation. This innovative platform holds promise as a dual-functional agent for siRNA-based gene silencing and RT enhancement in cancer therapy.