The interplay between the extracellular matrix and extracellular vesicle-associated microRNAs

The extracellular matrix (ECM) is a dynamic and bioactive structure that provides both physical scaffolding and regulatory cues essential for tissue homeostasis, development, and disease. In parallel, extracellular vesicles (EVs) and their associated microRNAs (miRNAs) have emerged as critical mediators of intercellular communication, influencing diverse physiological and pathological processes. Increasing evidence highlights a reciprocal interplay between the ECM and EV-miRNAs: the ECM regulates EV biogenesis, miRNA sorting, transport, and uptake, while EV-miRNAs modulate ECM composition, remodeling, and mechanobiology. This bidirectional crosstalk has profound implications for tissue repair, fibrosis, and cancer progression, where aberrant ECM-EV-miRNA signaling contributes to matrix stiffening, immune modulation, angiogenesis, and metastasis. Recent findings demonstrate that ECM mechanics and biochemical factors dictate EV cargo profiles and delivery efficiency, whereas EV-miRNAs regulate the expression of ECM proteins and remodeling enzymes, thereby shaping the microenvironment. Despite significant advances, the molecular mechanisms underlying ECM-governed miRNA trafficking and EV-miRNA-driven ECM remodeling remain incompletely understood. A deeper mechanistic understanding of ECM-EV-miRNA interactions will not only shed light on fundamental aspects of microenvironmental signaling but also open new avenues for the development of ECM- and EV-based therapies for regenerative medicine and cancer treatment.