Irreversible electroporation (IRE) remodels the tumor microenvironment (TME) toenhance biomaterial and nanoparticle (NP) delivery and immune activation, makingcombinational IRE-nanomedicine a promising approach for effective cancer treatment.Biomaterials Research Manuscript Template Page 2 of23Here, we present a rational combination strategy that integrates IRE-induced immunemodulation with M1 macrophage membrane-coated (M1-m) nanogels to amplify andprolong antitumor immune responses. Transcriptomic and immunological profiling afterIRE revealed a transient upregulation of immune and inflammatory pathways, particularlythe recruitment of macrophages and dendritic cells, followed by a rapid decline over time.To exploit this transient inflammatory state, we engineered M1-macrophage membranecoated nanogel hydrogel co-loaded with graphene quantum dots (GQDs) as a fluorescenceprobe and the immune modulator zoledronic acid (ZOL) (M1-GAZ). The IRE-enhancedtumor targeting efficiency of M1-m-coated NPs was confirmed by comparing the tumortargeting efficiency with other NP formulations including Au NPs (negatively orpositively charged), lipid-based NPs (liposomes and lipid NPs, negatively or positivelycharged), and macrophage (M0 or M1) cell membrane–coated NPs. Subsequently, thecombination of IRE with intravenously injected M1-GAZ significantly increased theinfiltration of activated macrophages and dendritic cells, resulting in superior tumorsuppression and prolonged survival compared to monotherapies. This study demonstratesthat engineering biomimetic M1-m-coated nanogels to synergize with IRE-induced TMEremodeling enables selective delivery and durable immune activation, providing a robustplatform for synergistic IRE cancer immunotherapy