Biomimetic Nanoplatform for Fibrosis Remodeling and Anti-PD-1 Potentiation via Cu+/Ca2+ Ion Dysregulation and TGF-β Inhibition in PDAC

Pancreatic ductal adenocarcinoma (PDAC) remains refractory to immunotherapy, largely due to the dense fibrotic stroma that promotes immune evasion and restricts drug penetration. Here, we report a multifunctional biomimetic nanoplatform (RPm@CC-LY) that simultaneously remodels the fibrotic tumor microenvironment and potentiates antitumor immunity. RPm@CC-LY achieves efficient tumor accumulation and effectively attenuates fibrosis through sustained release of Transforming growth factor-β (TGF-β) inhibitor LY2157299 (LY). Concurrently, intracellular acid-triggered degradation induces Cu+-mediated Fenton-like reactions and Ca2+ overload, leading to oxidative stress, mitochondrial dysfunction, and tumor cell apoptosis. In parallel, RPm@CC-LY reprograms tumor-associated macrophages (TAMs) toward an M1 phenotype and enhances dendritic cell maturation, thereby promoting robust CD8+ T cell infiltration. Notably, when combined with anti-PD-1 (αPD1) therapy, RPm@CC-LY induces a systemic immune response in mice. This work establishes a synergistic nanotherapeutic strategy that integrates fibrosis remodeling with ion interference therapy to overcome the immunotherapeutic barriers posed by fibrosis in PDAC.