Adipose stem cell-derived nanovesicles for cardioprotection: production and identification of therapeutic components

Abstract

Extracellular vesicles (EVs) derived from stem cells have shown therapeutic benefits in myocardial injury. However, the challenges in their large-scale production and elusive molecular mechanisms underlying their therapeutic effects have been hindering their clinical translation. Here, in a mouse model of myocardial ischemia-reperfusion, EVs isolated from human adipose tissue and EV-like nanovesicles fabricated with adipose stem cells (ADSCs) via a membrane extrusion approach, termed ADSC-derived nanovesicles (ADSC-CDNs), exhibited comparable cardioprotective effects, validating this EV-mimetic strategy. CDNs generated from the human monocytic cell line U937 similarly conferred protection, whereas those from HEK293 cells did not, highlighting the importance of cell source for therapeutic efficacy. microRNA profiling identified miR-24-3p as a predominant therapeutic cargo in ADSC-EVs and ADSC-CDNs. This microRNA upregulates the cytoprotective transcription factor Nrf2, thereby suppressing cardiomyocyte apoptosis. Functional assays also confirmed that miR-24-3p was a key component mediating the cardioprotective effects of those nanovesicles. Importantly, this study introduces a cell-source-dependent, scalable, and high-yield production platform for ADSC-CDNs that preserves molecular cargo profile of the parent cells, ensuring consistent therapeutic content. This EV-mimetic platform is technically feasible and clinically translatable, demonstrating reproducible efficacy in both acute injury and post-infarction recovery phases. Taken together, the defined microRNA cargo and the robust vesicle production strategy highlight the translational potential of ADSC-CDNs as an off-the-shelf cardioprotective therapy.