Nanoadjuvant‐Mediated Electro‐Immunotherapy Enhances Irreversible Electroporation for Pancreatic Cancer Treatment

Abstract

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, primarily attributable to its immunosuppressive tumor microenvironment and limited responsiveness to conventional therapies. Irreversible electroporation (IRE), a non‐thermal ablation technique, holds significant promise as it preserves critical peritumoral structures and can induce immunogenic cell death. However, the immunostimulatory effects elicited by IRE are typically transient, which constrains durable therapeutic benefit. To address this limitation, we developed an electro‐responsive nanoadjuvant system (PSFC) composed of peptide‐modified, superparamagnetic iron oxide (SPIO)‐encapsulated nanoparticles engineered to synergize with IRE. Upon IRE application, the PSFC nanoparticles undergo electro‐triggered disassembly, releasing CpG oligodeoxynucleotides (CpG ODNs) to amplify both innate and adaptive immune responses. This approach promotes antigen‐presenting cells’ activation and macrophage polarization toward an M1 phenotype, while enhancing intratumoral T cell activation and pro‐inflammatory cytokine secretion. By enabling spatiotemporal control of immune activation, this combined electro‐immunotherapeutic strategy effectively overcomes the inherent immuno‐resistance of PDAC and yields significantly improved treatment outcomes.