Redox-responsive copper-based nanoplatform enables efficient pancreatic ductal adenocarcinoma therapy via icaritin-enhanced cuproptosis

Redox-responsive ICMNs enable tumor-specific Cu 2+ / Icaritin co-delivery. • Released Icaritin amplifies cuproptosis via ROS generation, and GSH depletion. • ICMNs triggers immunogenic cell death and activates antitumor immunity. • ICMNs inhibits tumor growth, extends survival, and lacks systemic toxicity. Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited therapeutic options, largely due to its metabolic adaptability and immunosuppressive tumor microenvironment. Cuproptosis has emerged as a promising therapeutic strategy, however, its efficacy in solid tumors is constrained by intracellular redox buffering and insufficient bioavailable copper. Here, we developed a redox-responsive copper-based nanoplatform (ICMNs) by integrating icaritin (ICA) into a copper metal-organic framework to synergistically induce cuproptosis and immunotherapy. After cell internalization, ICMNs underwent glutathione (GSH)-triggered disassembly, co-releasing Cu 2+ and ICA. Mechanistically, ICMNs elevated intracellular reactive oxygen species levels by ∼ 145-fold while depleted GSH by 56%, thereby amplifying oxidative stress and mitochondrial dysfunction. Furthermore, ICMNs triggered prominent immunogenic cell death, evidenced by a 5.4-fold increase in calreticulin exposure, enhanced HMGB1 release, and ATP secretion, which promoted dendritic cell maturation and CD8 + T-cell activation. In patient-derived organoids, ICMNs reduced organoid viability by over 85%. In PDAC KPC subcutaneous transplant tumor mouse models, ICMNs achieved an 85.6% tumor inhibition rate and significantly prolonged median survival (41.5 vs. 15 days) without obvious systemic toxicity. Collectively, our findings demonstrate that redox potentiates copper-induced tumor cell death and antitumor immunity, offering a promising nanotherapeutic strategy for PDAC treatment. Download: Download high-res image (159KB) Download: Download full-size image