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

Adv Mater. 2023 Jun;35(23):e2210691. doi: 10.1002/adma.202210691. Epub 2023 Apr 25.

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.

Keywords: cardiomyocyte regeneration; charge reversal; hybrid cell-membrane coatings; myocardial ischemia reperfusion injury; siRNA delivery.

MeSH terms

  • Animals
  • Apoptosis
  • Biomimetics
  • Myocardial Reperfusion Injury* / metabolism
  • Myocardial Reperfusion Injury* / therapy
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism
  • RNA, Small Interfering / metabolism
  • Rats
  • Swine

Substances

  • RNA, Small Interfering