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

To enhance the efficiency of tumor ablation, we propose the novel pulse configuration nμPEF, which combines both nanosecond and microsecond pulses. This advancement aims to further the potential application of irreversible electroporation (IRE) in oncological therapy. We demonstrated that nμPEF exhibited enhanced efficacy in inducing immunogenic cell death, positioning it as a promising candidate for the next generation of ablative therapy. However, the immune response induced by nμPEF alone was found to be insufficient in effectively suppressing abscopal tumors. Leveraging the advantageous properties of nanobiomaterials as modular platforms for targeted and controlled delivery of diverse agents, we subsequently developed a genetically engineered nanovesicle, designated PPR@CM-PD1, as an immunomodulatory agent to enhance the "in situ" vaccination response triggered by nμPEF. The encapsulation of the immune adjuvant imiquimod (R837) within a PEG-PLGA nanoparticle, followed by coating with a layer of genetically engineered cell membrane expressing the PD1 protein, enabled PPR@CM-PD1 to target both the innate immune system via TLR7 agonism and the adaptive immune system via PD1/PDL1 checkpoint blockade. In a reciprocal response, nμPEF modulated the tumor stroma to enhance intratumoral infiltration of PPR@CM-PD1. The combination of nμPEF and PPR@CM-PD1 elicited a potent and systemic antitumor immune response, resulting in a remarkable suppression of both nμPEF-treated and untreated distant tumors (abscopal effects) - an outcome not observed with either nμPEF or PPR@CM-PD1 alone. Overall, this interdisciplinary synergistic approach offers a new perspective for oncotherapy and holds promising prospects for clinical application. This article is protected by copyright. All rights reserved.