siRNA delivery against myocardial ischemia reperfusion injury mediated by reversibly camouflaged biomimetic nanocomplexes.

siRNA-mediated management of myocardial ischemia reperfusion (IR) injury is greatly hampered by the inefficient myocardial enrichment and cardiomyocyte transfection. Herein, nanocomplexes (NCs) reversibly camouflaged with platelet-macrophage hybrid membrane (HM) were developed to efficiently deliver Sav1 siRNA (siSav1) into cardiomyocytes, suppressing the Hippo pathway and inducing cardiomyocyte regeneration. The biomimetic BSPC@HM NCs consisted of a cationic nano-core assembled from a membrane-penetrating helical polypeptide (P-Ben) and siSav1, a charge-reversal intermediate layer of poly( L -lysine)-cis-aconitic acid (PC), and an outer shell of HM. Due to HM-mediated inflammation homing and microthrombus targeting, intravenously injected BSPC@HM NCs could efficiently accumulate in the IR-injured myocardium, where the acidic inflammatory microenvironment triggered charge reversal of PC to shed off both HM and PC layers and allow the penetration of the exposed P-Ben/siSav1 NCs into cardiomyocytes. In rats and pigs, BSPC@HM NCs remarkably down-regulated Sav1 in IR-injured myocardium, promoted myocardium regeneration, suppressed myocardial apoptosis, and recovered cardiac functions. This study reports a bio-inspired strategy to overcome the multiple systemic barriers against myocardial siRNA delivery, and holds profound potentials for gene therapy against cardiac injuries. This article is protected by copyright. All rights reserved.