Spatiotemporal Nanotherapy After Myocardial Infarction: Targeting the Inflammatory-to-reparative Transition With...

Post-myocardial infarction (MI) healing is a moving sequence of injury, inflammatory clearance, resolution, vascular repair, and scar maturation. This review evaluates how extracellular vesicles (EVs), cell-derived nanovesicles, and engineered nanoparticles can be matched to these changing biological requirements.

A critical narrative synthesis was organized around four approximate post-MI windows: minutes to 24 h, days 1-3, days 3-7, and after day 7. Representative mechanistic, rodent, porcine, and human studies were compared by target cell, cargo, material, release profile, route, quantitative delivery evidence, efficacy, and translational liability.

Early oxidative and microvascular injury favors brief cytoprotection and vascular targeting; the inflammatory peak favors calibrated control of recruited leukocytes while preserving debris removal; resolution favors efferocytosis, reparative immune signaling, angiogenesis, and local immunomodulation; and later remodeling favors selective rather than global antifibrotic therapy. Directly generated nanovesicles and modified-mRNA lipid nanoparticles expand the design space. However, human evidence remains sparse, and most preclinical studies use fixed schedules, young non-comorbid rodents, qualitative biodistribution, and incompletely defined potency assays.

A credible spatiotemporal product must demonstrate phase-dependent target availability, controlled exposure, target-cell cargo engagement, and reduced benefit or emerging harm with a deliberately mismatched schedule. Translation requires quantitative pharmacokinetics and biodistribution, route-specific safety, mechanism-linked potency, scalable manufacturing, and validation in reperfused comorbid large-animal models.