Lesion core is the area with the most serious injury and vigorous repair. Existing nanocarriers are difficult to break through the targeted delivery to lesion core and the precise treatment for intracellular and extracellular microenvironment. Herein, a cellular membrane-engineered nanovesicle (CMEV) with hierarchical structure is constructed using double emulsion-extrusion method, by integrating neutrophil membrane, functional antibody and gelled drug-loaded core, as 'three-stage booster' to target the lesion core and deliver catestatin (CST), a small therapeutic peptide, for ischemic cardiomyopathy therapy. By coating neutrophil membrane outside the shell, CMEV is endowed with the function of neutrophil-like migration to achieve the first stage of tissue targeting. Based on the specific anchoring to injured myocardium, myosin light chain 3 (MLC3) antibody was embedded to fulfill the second stage of CMEV accumulation in lesion core. The gelled core containing CST-sodium alginate (NaAlg) with pH-responsive shell is prepared by ionic cross-linking to accomplish the third stage of precise CST administration. Triggered by the microenvironment, NaAlg electrostatically adheres to the lesion core for sustained release, enhancing the efficacy of CST in improving cardiomyocyte apoptosis, excessive fibrosis, macrophage polarization and angiogenesis. Thus, the "three-stage booster" nanovesicle significantly ameliorates cardiac function and adverse remodeling to treat ischemic cardiomyopathy. This article is protected by copyright. All rights reserved.