Abstract

Mimicking endogenous immune cell responses holds great promise for repairing tissue damage in myocardial infarction (MI), yet challenges persist due to the heterogeneity, spatiotemporal dynamics, and diverse functions of macrophage subtypes during post-MI repair. Herein, we introduce a data-driven biomimetic strategy that leverages the sequential delivery of immune cell-mimicking nanoparticles to replicate the natural immune repair mechanisms. Using single-cell RNA sequencing, we analyzed the dynamic changes in immune cells during post-MI repair, revealing the distinct roles of macrophage subtypes in different stages of recovery. Building on these insights, we developed immune cell-mimicking nanoparticles and devised a sequential delivery strategy to emulate the temporal distribution of three macrophage subtypes (M2a, M2b, and M2c) throughout the MI repair process. Our results demonstrated that each macrophage subtype played a unique and time-dependent role in the repair process. Among various delivery strategies tested, the sequential delivery of M2a, M2b, and M2c nanoparticles emerged as the most effective approach for promoting MI recovery. This study not only provides an innovative framework for the design and application of immune cell-mimicking nanoparticles in MI treatment but also underscores the importance of replicating natural healing processes in nanomedicine development.