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

ABSTRACT 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.