Biomimetic Nanogels Programmed for Irreversible-Electroporation-Primed Tumor Microenvironments to Elicit Durable Antitumor Immunity.

Irreversible electroporation (IRE) remodels the tumor microenvironment to enhance biomaterial and nanoparticle (NP) delivery and immune activation, making combinational IRE-nanomedicine a promising approach for effective cancer treatment. Here, we present a rational combination strategy that integrates IRE-induced immune modulation with M1 macrophage-membrane (M1-m)-coated nanogels to amplify and prolong antitumor immune responses. Transcriptomic and immunological profiling after IRE revealed a transient up-regulation of immune and inflammatory pathways, particularly the recruitment of macrophages and dendritic cells, followed by a rapid decline over time. To exploit this transient inflammatory state, we engineered an M1-m-coated nanogel hydrogel co-loaded with graphene quantum dots as a fluorescence probe and the immune modulator zoledronic acid (M1-GAZ). The IRE-enhanced tumor-targeting efficiency of M1-m-coated NPs was confirmed by comparing the tumor-targeting efficiency with other NP formulations including gold NPs (negatively or positively charged), lipid-based NPs (liposomes and lipid NPs, negatively or positively charged), and macrophage (M0 or M1) cell-membrane-coated NPs. Subsequently, the combination of IRE with intravenously injected M1-GAZ markedly increased the infiltration of activated macrophages and dendritic cells, resulting in superior tumor suppression and prolonged survival compared to monotherapies. This study demonstrates that engineering biomimetic M1-m-coated nanogels to synergize with IRE-induced tumor microenvironment remodeling enables selective delivery and durable immune activation, providing a robust platform for synergistic IRE cancer immunotherapy.