An injectable SFMA/HA-E hydrogel for sustained delivery of hucMSC-derived exosomes promotes myocardial repair after infarction

BACKGROUND: Myocardial infarction (MI) causes permanent loss of cardiomyocytes and heart failure. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSCs-Exos) have shown therapeutic potential. Still, their clinical utility is limited by rapid systemic clearance, highlighting the need for a delivery system to achieve sustained release and effect. METHODS: We fabricated an injectable, photopolymerizable hydrogel consisting of silk fibroin methacrylate (SFMA) and epigallocatechin gallate-grafted hyaluronic acid (HA-E) to encapsulate hucMSC-Exos (SFMA/HA-E+Exos). Therapeutic effects were assessed in a rat MI model using echocardiography, histology, and molecular analysis. RESULTS: The SFMA/HA-E hydrogel exhibited favorable mechanical properties, controllable degradation, and sustained exosome release. In vitro, hucMSC-Exos promoted cell survival, migration, and tube formation under hypoxic conditions. In vivo, a single intramyocardial injection of SFMA/HA-E+Exos significantly improved cardiac function compared with the PBS-treated MI group (LVEF: 70.71 ± 3.04% vs. 30.75 ± 3.55%), reduced fibrosis, and suppressed cardiomyocyte apoptosis. The treatment also reinforced angiogenesis, as indicated by increased numbers of CD31⁺ and α-SMA⁺ vessels, induced a pro-reparative immune microenvironment by shifting macrophages polarization towards the M2 phenotype, and up-regulated the gap junction protein Connexin 43. CONCLUSION: The SFMA/HA-E hydrogel-mediated delivery of hucMSC-Exos provides potent dual therapy through structural support and bioactive signaling, inhibiting adverse remodeling and inducing cardiac repair after MI, and represents a potential therapeutic approach for ischemic heart disease.