MicroRNA-208a silencing against myocardial ischemia/reperfusion injury mediated by reversibly camouflaged biomimetic nanocomplexes

MicroRNA-208a (miR-208a) plays critical roles in the severe fibrosis and heart failure post myocardial ischemia/reperfusion (IR) injury. MiR-208a inhibitor (mI) with complementary RNA sequence can silence the expression of miR-208a, while it is challenging to achieve efficient and myocardium-targeted delivery. Herein, biomimetic nanocomplexes (NCs) reversibly coated with red blood cell membrane (RM) were developed for the myocardial delivery of mI. To construct the NCs, membrane-penetrating helical polypeptide (PG) was first adopted to condense mI and form the cationic inner core, which subsequently adsorbed catalase (CAT) via electrostatic interaction followed by surface coating with RM. The membrane-coated NCs enabled prolonged blood circulation after systemic administration, and could accumulate in the injured myocardium via passive targeting. In the oxidative microenvironment of injured myocardium, CAT decomposed H₂O₂ to produce O₂ bubbles, which drove the shedding of the outer RM to expose the positively charged inner core, thus facilitated effective internalization by cardiac cells. Based on the combined contribution of mI-mediated miR-208a silencing and CAT-mediated alleviation of oxidative stress, NCs effectively ameliorated the myocardial microenvironment, hence reducing the infarct size as well as fibrosis and promoting recovery of cardiac functions. This study provides an effective strategy for the cytosolic delivery of nucleic acid cargoes in the myocardium, and it renders an enlightened approach to resolve the blood circulation/cell internalization dilemma of cell membrane-coated delivery systems.