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

Abstract

ABSTRACT 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.