Targeted delivery of engineered adipose-derived stem cell secretome to promote cardiac repair after myocardial infarction

Stem cell secretome offers a promising alternative to stem cell transplantation for treating myocardial infarction (MI). However, its clinical application faces two major challenges: how to enhance the levels of growth factors within the secretome to promote cardiac cell survival and vascularization, and how to efficiently deliver the secretome to the infarcted heart during the acute MI phase without risking rupture of the weakened myocardium. To address these challenges, we upregulated angiogenic growth factors in the secretome from adipose-derived stem cells (ADSC-secretome) by conditioning the cells under hypoxia and with insulin-like growth factor 1 (IGF-1). Our results show that exposure to 1 % O₂ condition significantly increased the expression of VEGF, bFGF, and PDGF-BB compared to 5 % O₂ condition. Co-treatment with IGF-1 further elevated the levels of these growth factors and, notably, reduced the secretion of pro-inflammatory cytokines such as TNFα, IL-1β, and IL-6 from the ADSCs. To rapidly and specifically deliver the secretome to the infarcted heart during acute MI, we encapsulated it within ischemia-targeting nanoparticles. These nanoparticles, designed for intravenous injection, preferentially accumulated in the infarcted region. The treatment significantly improved cardiac cell survival, tissue vascularization, and cardiac function. These findings suggest that ADSC secretome, enriched with angiogenic growth factors, holds strong potential for facilitating cardiac repair following MI.