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.