Injectable sustained-release danshensu sodium-loaded nanoparticle hydrogel targets macrophages to improve myocardial microenvironment for myocardial infarction treatment

Myocardial infarction (MI) induces cardiomyocyte necrosis, inflammation, fibrosis, and ventricular remodeling, leading to heart failure. To address this, we developed an intelligent cardiac patch, SMM@Gel, composed of a reactive oxygen species (ROS)-responsive PVA-TSPBA hydrogel matrix reinforced via solvent exchange and salting-out technology, loaded with mannose-functionalized, danshensu sodium-loaded hollow mesoporous polydopamine nanoparticles (Sa@mPDA-Man). This design makes sustained drug release and ROS scavenging come true. In vitro, studies demonstrated SMM@Gel promoted endothelial tube formation (24 ± 3 nodes vs. 6 ± 2 in controls) and M2 macrophage polarization (CD206+ cells) while reducing inflammation (iNOS downregulation). In vivo, experiments in MI rats revealed SMM@Gel preserved left ventricular ejection fraction (LVEF: 52.3 % ± 4.1 % vs. 38.5 % ± 3.2 % in the saline group), normalized ventricular dimensions (EDV/ESV) and enhanced wall thickness. Histological analysis showed reduced infarct size (18.7 % ± 2.5 % vs. 32.1 % ± 3.8 %), decreased inflammation, and improved neovascularization. RNA-seq identified pathways linked to angiogenesis, inflammation resolution, and extracellular matrix remodeling. These findings highlight SMM@Gel's potential as a dual-action therapy for MI, combining ROS scavenging, anti-inflammatory effects, and angiogenic promotion to mitigate post-MI remodeling and preserve cardiac function. • ROS-Responsive Drug Delivery :Sa@mPDA-Man NPs release danshensu in infarcts via ROS-sensitive hydrogel (local antioxidative, anti-inflammatory, ROS-scavenging). • Multifunctional Regeneration:Promotes cell recruitment, vascular growth, M2 polarization (reduces fibrosis, enhances angiogenesis, improves repair). • Mechanical / Biocompatibility :Solvent exchange/salting-out ensures robust mechanics, excellent biocompatibility. • Preserved Cardiac Function :In MI rats, maintains LVEF, reduces EDV/ESV, increases wall thickness, halts heart failure.