A Bismuth-Based Metal-Phenolic Nanocoordinator Blocks TGF‑β to Reverse Immunosuppression for Potentiated Hepatocellular Carcinoma Radioimmunotherapy

Radiotherapy triggers an adaptive upregulation of transforming growth factor-β (TGF-β), which paradoxically promotes radioresistance by reinforcing the stromal barrier, suppressing immunity and accelerating DNA repair. To overcome these limitations, we engineered a multifunctional nanocoordinator (ASO TGF /MPN-aPD-L1) by leveraging the multimodal molecular interaction of bismuth-phenolic networks, creating an “all-in-one” platform that densely encapsulates TGF-β antisense oligonucleotides (ASO TGF ) via metal coordination and π–π stacking while adsorbing aPD-L1 on the surface for sensitizing radio-immunotherapy. Mechanistically, the bismuth component acts as a high-Z radiosensitizer to amplify initial DNA damage, while ASO TGF concurrently blocks TGF-β signaling by inhibiting its translation. This dual action not only abrogates DNA repair pathways but also suppresses cancer-associated fibroblasts (CAFs) activation and remodels the extracellular matrix (ECM) to facilitate cytotoxic T cell infiltration. Furthermore, surface-adsorbed aPD-L1 prevents T cell exhaustion, sustaining long-term antitumor immunity. Our results confirm that this strategy significantly alleviates tumor fibrosis, enhances CD8 + T cell infiltration, and potentiates radiotherapy efficacy in hepatocellular carcinoma models (HCC). Collectively, except for radiosensitization, by simultaneously targeting TGF-β signaling and PD-L1-mediated immune evasion, our nanocoordinator represents a promising strategy to potentiate radioimmunotherapy for HCC.