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.