siRNA Delivery against Myocardial Ischemia Reperfusion Injury Mediated by Reversibly Camouflaged Biomimetic Nanocomplexes

Abstract 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 a platelet–macrophage hybrid membrane (HM) are developed to efficiently deliver Sav1 siRNA (siSav1) into cardiomyocytes, suppressing the Hippo pathway and inducing cardiomyocyte regeneration. The biomimetic BSPC@HM NCs consist of a cationic nanocore 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 can efficiently accumulate in the IR‐injured myocardium, where the acidic inflammatory microenvironment triggers 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 downregulates Sav1 in IR‐injured myocardium, promotes myocardium regeneration, suppresses myocardial apoptosis, and recovers cardiac functions. This study reports a bioinspired strategy to overcome the multiple systemic barriers against myocardial siRNA delivery, and holds profound potential for gene therapy against cardiac injuries.