Stem Cell-derived Exosome Nebulization Therapy (SCENT) Improves Cardiac Function And Tissue Repair In Mice And Pigs

Stem cell-derived exosomes show promise as therapeutics for cardiac repair after injury. However, due to their short half-life in vivo, effective treatment typically requires repeated dosing. Previous methods for delivering exosomes to the heart involve invasive injection routes. Here, we report a noninvasive and repeatable approach to exosome delivery via inhalation after myocardial infarction (MI), called Stem Cell-derived Exosome Nebulization Therapy (SCENT). In a mouse model of MI, exosomes were recruited to the ischemic heart after repeated dosing via nebulization. SCENT ameliorated cardiac repair by significantly improving left ventricular function, reducing infarct size, and promoting cardiomyocyte proliferation. Further investigation via single-cell RNA sequencing of the mouse heart after SCENT revealed a significant downregulation of CD36 in endothelial cells (ECs). In an EC- Cd36 fl/- mouse model, we found that inhibiting CD36, a fatty acid transporter in ECs, led to a compensatory increase in glucose utilization in the heart and higher ATP generation, resulting in enhanced cardiac contractility. In a pig model of acute MI, we evaluated functional outcomes using cardiac magnetic resonance imaging (MRI) and found that SCENT led to reduced left ventricular (LV) end-systolic volume (ESV) at day 28 (19.07 ± 3.22 ml) compared to controls (23.60 ± 3.06 ml). Additionally, pigs treated with SCENT exhibited increased LV ejection fraction (EF) (59.36 ±2.84%) and fractional shortening (FS) (29.56 ± 1.25%), further confirming cardioprotection in pigs. Our results pave the way for development of a non-invasive exosome delivery method for rescuing heart injury.