MicroRNAs as key paracrine factors in stem cell therapy: Molecular mechanisms, therapeutic applications, and future perspectives.

Stem cell-derived microRNAs (miRNAs) have emerged as pivotal paracrine mediators in regenerative medicine, bridging the gap between cellular therapy and molecular precision. This review delineates the central role of miRNAs encapsulated within stem cell-derived extracellular vesicles (EVs) as key regulators of intercellular communication, orchestrating tissue repair, immune modulation, and disease resolution. By synthesizing recent advances, we highlight three core innovations: (1) Mechanistic insights: miRNAs drive angiogenesis, immunomodulation, and anti-apoptosis and anti-fibrosis effect, through targeted signaling pathways, demonstrating their ability to reprogram recipient cells post-transcriptionally. (2) Therapeutic breadth: EV-delivered miRNAs exhibit remarkable efficacy across cardiovascular, metabolic, renal, and musculoskeletal disorders, with engineered EVs enabling tissue-specific delivery and enhanced therapeutic potency. (3) Technological frontiers: Innovations in miRNA-loaded EVs, including CRISPR-based modifications and bioprinted tissue constructs, redefine regenerative strategies by integrating bioengineering with precision medicine. This work underscores the paradigm shift from cell replacement to miRNA-driven therapies, addressing critical scalability, standardization, and clinical translation challenges. Our analysis positions miRNAs as indispensable tools for next-generation regenerative therapies, offering transformative potential for diseases with unmet clinical needs.