An ischemic area-targeting, peroxynitrite-responsive, biomimetic carbon monoxide nanogenerator for preventing myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion (MI/R) injury is common in patients who undergo revascularization therapy for myocardial infarction, often leading to cardiac dysfunction. Carbon monoxide (CO) has emerged as a therapeutic molecule due to its beneficial properties such as anti-inflammatory, anti-apoptotic, and mitochondrial biogenesis-promoting properties. However, its clinical application is limited due to uncontrolled release, potential toxicity, and poor targeting efficiency. To address these limitations, a peroxynitrite (ONOO-)-triggered CO donor (PCOD585) is utilized to generate a poly (lactic-co-glycolic acid) (PLGA)-based, biomimetic CO nanogenerator (M/PCOD@PLGA) that is coated with the macrophage membrane, which could target to the ischemic area and neutralize proinflammatory cytokines. In the ischemic area, local produced ONOO- triggers the continuous release of CO from M/PCOD@PLGA, which efficiently ameliorates MI/R injury by clearing harmful ONOO-, attenuating the inflammatory response, inhibiting cardiomyocyte apoptosis, and promoting mitochondrial biogenesis. This study provides a novel insight into the safe therapeutic use of CO for MI/R injury by utilizing a novel CO donor combined with biomimetic technology. The M/PCOD@PLGA nanogenerator offers targeted delivery of CO to the ischemic area, minimizing potential toxicity and enhancing therapeutic efficacy.