Stem cell therapy, as a transformative approach in the field of regenerative medicine, has demonstrated tremendous potential in treating a wide range of diseases and injuries(Zakrzewski et al., 2019). Possessing dual capacities for self-renewal and multi-lineage differentiation, stem cells serve as crucial mediators in tissue regeneration, immunomodulation, and disease model development (Yamanaka, 2020). As of December 2024, a total of 116 regenerative stem cell clinical trials have been approved or completed globally(Abbott, 2025). However, a fundamental paradigm shift has occurred in recent years: a growing body of evidence indicates that the therapeutic effects of stem cells are primarily derived not from their differentiation and replacement after engraftment, but rather through their potent paracrine mechanisms (Murphy et al., 2013).

This paracrine communication is predominantly mediated by EVs secreted by stem cells (Han et al., 2022). These EVs, particularly exosomes, act as natural “nanoscale messengers,” responsible for precisely delivering a variety of bioactive molecules to target cells. Among the diverse cargoes carried by EVs—including proteins, lipids, and other nucleic acids—miRNAs, which can regulate approximately 30 %–70 % of human gene expression(Lu and Clark, 2012), have emerged as the most functionally critical effector molecules. miRNAs are a class of short, non-coding RNAs, approximately 22 nucleotides in length, that act as “molecular switches” by binding to target mRNAs to inhibit their translation or promote degradation, thereby precisely regulating the gene expression networks of recipient cells (Mori et al., 2019). This mechanism allows stem cells to remotely orchestrate complex cellular behaviors, such as proliferation, apoptosis, and inflammation, in injured tissues.

The discovery that stem cells deliver miRNAs by secreting EVs represents a major advancement, which shifts the focus of stem cell therapy from a “cell-based” strategy to a “cell-free,” molecularly-driven strategy. This approach holds significant promise for overcoming the limitations of traditional cell transplantation, such as low survival rates and potential immunogenicity(Shan et al., 2024; Xue et al., 2024). Therefore, this review will focus on miRNA as the key paracrine factor in stem cell therapy. We will systematically elucidate its molecular mechanisms of action, summarize its therapeutic applications in various disease models, and provide an outlook on future research directions and prospects for clinical translation.