“Ferrero-like” nanoparticles knotted injectable hydrogels to initially scavenge ROS and lastingly promote vascularization in infarcted hearts

Abstract

Myocardial infarction (MI) exhibits a complicated and ever-accelerated pathological change involving excessive reactive oxygen species (ROS) and the up-regulation of pro-inflammatory cytokines in the initial stage, and a permanently inadequate blood supply. Herein, an injectable hydrogel fabricated by nanoparticles (NPs) knotted thiolated hyaluronic acid (HA-SH) was reported to reverse the hostile microenvironment and rebuild the heart functions after MI Inspired by the composite shell-core structure of Ferrero chocolate sphere, a mimetic nanocarrier was designed to consist of the hydrophobic dimethyloxalylglycine (DMOG) NPs core and a thick polydopamine (PDA) shell formed by the self-polymerization of dopamine embedded with water-soluble drug epigallocatechin-3-gallate (EGCG) through π-π interactions. The resulted “Ferrero-like” NPs exhibited a “three-in-one” capacity, namely loading two distinct drugs, elimination of ROS, and serving a crosslinker to knot HA-SH. “Ferrero-like” NPs and HA-SH could rapidly form a hydrogel that exhibited a stable mechanical property, high capability to capture ROS, and programmed release of EGCG and DMOG. Four weeks after deploying the “Ferrero-like” NPs knotted hydrogels into rat infarcted hearts, the ejection fraction (EF) increased by 23.7%, and the infarct size decreased by 21.1%, and the fibrotic area reduced by 24.4%. The outcomes of immunofluorescence staining and reverse transcription-polymerase chain reaction (RT-PCR) demonstrated a down-regulation of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interferon-γ (IFN-γ)), up-regulation of vascular related growth factors (hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor A (VEGFA), von Willebrand factor (vWF), angiopoietin-1 (Ang-1)) and cardiac-related mRNAs (gap junction protein (C×43), Cadherin 2). All in all, in this report, a very simple approach to intertemporally address the intricate and ongoing pathological changes after MI by injecting “Ferrero-like” NPs knotted hydrogels is developed to reverse hostile microenvironment, with an ability to scavenge ROS, down-regulate pro-inflammation factors in the first stage, and promote angio-genesis in a long term, thereby contributing to a significant improvement of heart functions.