A Photocurable Hydrogel Cardiac Patch Incorporating Formononetin-Loaded Lipid Nanoparticles for Myocardial Repair After Acute Ischemia.

Myocardial infarction (MI) induces ventricular dysfunction through ischemic necrosis and fibrotic remodeling, progressing to heart failure and constituting a major global cardiovascular burden. To address this, we developed a photocurable, hydrogel-based cardiac patch (Gel-CS/FMN@LNP hydrogel) with favorable mechanical robustness. The patch is composed of methacryloylated carboxymethyl chitosan (CACSMA) and methacryloylated gelatin (GelMA), incorporating Formononetin-loaded lipid nanoparticles (FMN@LNPs) for myocardial restoration. In vitro studies demonstrated that the Gel-CS/FMN@LNP hydrogel not only inhibited cardiomyocyte apoptosis by scavenging reactive oxygen species (ROS) but also promoted migration and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, when a co-culture system of the Gel-CS/FMN@LNP hydrogel and heart-forming organoids (HFOs) was subjected to oxygen-glucose deprivation (OGD) conditions, the system effectively inhibited HFO apoptosis and suppressed HFO fibrosis. In vivo experiments in MI model rats revealed that the Gel-CS/FMN@LNP hydrogel group preserved a higher left ventricular ejection fraction (LVEF: 67.2 ± 1.9%) compared to the MI group (LVEF: 41.7 ± 4.7%) at 28 days post-MI, thereby improving cardiac function. Histological analysis showed that the Gel-CS/FMN@LNP hydrogel reduced myocardial fibrosis in the infarct border zone, promoted angiogenesis, and facilitated macrophage polarization toward the M2 phenotype. RNA sequencing (RNA-seq) identified pathways associated with metabolic regulation (PPAR signaling pathway), myocardial protection (PI3K-Akt signaling pathway), anti-fibrosis (inhibition of extracellular matrix remodeling), and anti-inflammatory immune regulation (TNF signaling pathway). Single-cell RNA sequencing (scRNA-seq) revealed that the Gel-CS/FMN@LNP hydrogel promoted post-MI cardiac repair through a multi-target network involving circadian rhythm remodeling, matrix regulation, immune balance, and vascular protection. Our hydrogel system, which combines facile injectability, sustained release of active factors, and synergistic therapeutic effects, represents a promising therapeutic approach for post-MI repair.