A copper nanoplatform with irreversible electroporation induces cuproptosis via lipid reprogramming and remodels tumor immunity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most treatment-refractory malignancies, largely due to its dense stromal architecture and limited intratumoral drug penetration. Here, we developed a hyaluronic acid-modified polypyrrole-copper nanoparticle (PLGA-Cuppy@HA, mCuppy) for copper delivery and irreversible electroporation (IRE)-assisted therapy. To optimize therapeutic performance, copper loading and HA surface modification were systematically tuned, resulting in a formulation with balanced physicochemical properties, efficient CD44-mediated cellular uptake, and favorable biological activity. When combined with IRE, mCuppy exhibited enhanced intratumoral retention, improved 3D spheroid penetration, and increased intracellular uptake, which were associated with IRE-induced membrane permeabilization and improved intratumoral distribution. Mechanistically, integrated transcriptomic and metabolomic analyses revealed that the combination treatment induced profound metabolic reprogramming associated with cuproptosis, including dysregulation of pantothenate/CoA biosynthesis, unsaturated fatty acid metabolism, and glycerolipid metabolism. These alterations were accompanied by lipoylated protein aggregation, lipid droplet accumulation, and mitochondrial dysfunction. Notably, additional analyses of cell death pathways suggested that, while cuproptosis represents a dominant mechanism, apoptosis and lipid metabolism-associated stress responses may also contribute to the overall therapeutic effect. In orthotopic PDAC models, mCuppy combined with IRE achieved marked tumor suppression and promoted antitumor immune remodeling, including dendritic cell maturation, increased CD8+ T-cell infiltration, and M1 macrophage polarization. Together, this study demonstrates that IRE-potentiated copper nano therapy induces metabolic vulnerability, cuproptosis, and immune remodeling in PDAC, providing a promising strategy for stromal-rich pancreatic cancer.