Abstract
Myocardial infarction (MI) remains a leading cause of heart failure, and current therapies fail to prevent cardiomyocyte loss or support effective tissue regeneration. Injectable hydrogels (HGs) have emerged as promising platforms for delivering therapeutic cues and structural support; however, few systems simultaneously integrate vascular guidance and RNA therapeutics. Here, we have developed a thermosensitive alginate-collagen HG pre-vascularized with endothelial cells and fibroblasts and engineered for the sustained release of cardioprotective miR-133a encapsulated in ionizable lipid nanoparticles (LNPs). MiR-133a-LNPs formulated by microfluidics display optimal physicochemical properties, efficient endosomal escape and preserved bioactivity. The HG exhibits shear-thinning, self-healing behavior and temperature-triggered gelation, enabling minimally invasive delivery and controlled miRNA release. Embedded cells remain viable, organized into early microvascular networks, and secrete pro-angiogenic factors. MiR-133a released from the HG attenuates oxidative stress-induced apoptosis in cardiomyoblasts. This multifunctional platform integrates structural support, pro-angiogenic signaling and sustained anti-apoptotic miRNA delivery, offering a promising strategy to mitigate early myocardial injury and promote key regenerative processes following MI.