Optimal Irreversible Electroporation Combined with Nano‐Enabled Immunomodulatory to Boost Systemic Antitumor Immunity

Abstract In this work, we proposed nµPEF, a novel pulse configuration combining nanosecond and microsecond pulses (nµPEF), to enhance tumor ablation in irreversible electroporation (IRE) for oncological therapy. nµPEF demonstrated improved efficacy in inducing immunogenic cell death, positioning it as a potential candidate for next‐generation ablative therapy. However, the immune response elicited by nµPEF alone was insufficient to effectively suppress distant tumors. To address this limitation, we developed PPR@CM‐PD1, a genetically engineered nanovesicle. PPR@CM‐PD1 employed a polyethylene glycol‐polylactic acid‐glycolic acid (PEG‐PLGA) nanoparticle encapsulating the immune adjuvant imiquimod and coated with a genetically engineered cell membrane expressing programmed cell death protein 1 (PD1). This design allowed PPR@CM‐PD1 to target both the innate immune system through toll‐like receptor 7 (TLR7) agonism and the adaptive immune system through programmed cell death protein 1/programmed cell death‐ligand 1 (PD1/PDL1) checkpoint blockade. In turn, nµPEF facilitated intratumoral infiltration of PPR@CM‐PD1 by modulating the tumor stroma. The combination of nµPEF and PPR@CM‐PD1 generated a potent and systemic antitumor immune response, resulting in remarkable suppression of both nµPEF‐treated and untreated distant tumors (abscopal effects). This interdisciplinary approach presents a promising perspective for oncotherapy and holds great potential for future clinical applications.