Conductive Microneedle Patch with Mitochondria‐Localized Generation of Nitric Oxide Promotes Heart Repair after Ischemia‐Reperfusion Therapy

Timely blood resupply is a clinical strategy to treat myocardial infarction, which unavoidably causes myocardial ischemia-reperfusion injury. With disturbed electrical conduction and oxidative stress in infarcted myocardium, injured heart experiences a negative ventricle remodeling process, and finally leads to heart failure. Nitric oxide (NO) is a short-lived signaling molecule regulating cardiovascular homeostasis, while vasodilation of systemic vasculature is accompanied by its exogenous supplementation. Meanwhile, connexin 43 (Cx43), a gap junction protein for electrical propagation in myocardium, is downregulated by NO derived from inducible nitric oxide synthase (iNOS). The seesaw-like relationship of Cx43 and NO in cardiac repair raises an intractable issue of how to address localized-specific NO administration and simultaneously reconstruct electrical conduction. Given that both iNOS accumulation and NO metabolism affected by oxidative stress occur in mitochondria, mitochondria-specific l-arginine (l-Arg) delivery systems are developed and are encapsulated in conductive microneedle patches. When implanted onto myocardium, l-Arg is catalyzed by iNOS to synthesize NO in mitochondria, which contributes to sustained NO administration and alleviates oxidative stress. Functional patch with equivalent conductivity to myocardium repairs electrophysiological properties of heart and upregulates Cx43 expression. This study proposes integration of in situ NO generation and electrical conduction reconstruction in cardiac repair.