Matrix-bound extracellular vesicles

Abstract

Extracellular vesicles (EVs) are key mediators of intercellular communication, carrying bioactive cargo that can reprogramme cellular states in health and disease. EVs can be conceptualized by spatial distribution and site of action as liquid-phase EVs, which disseminate through biofluids and support systemic signalling, and matrix-bound EVs, which are retained within the extracellular matrix to enable site-specific, context-dependent signalling. Research on liquid-phase EVs has driven biomarker discovery, clarified disease mechanisms and enabled the development of EV-based therapeutic strategies. In contrast to liquid-phase EVs, which circulate and are subject to dilution, clearance and non-specific biodistribution, matrix-bound EVs act as spatially confined reservoirs of molecular cargo that encode local tissue states in both homeostasis and disease. In this Review, we position matrix-bound EVs within the broader EV landscape and examine their defining properties and roles in tissue homeostasis and disease pathogenesis. We discuss opportunities to harness matrix-bound EVs for tissue engineering, diagnostic and therapeutic applications, and outline key translational challenges. This framework aims to guide the development of diagnostic and therapeutic platforms that leverage the distinct biological functions of matrix-bound EVs. Extracellular vesicles (EVs) are central mediators of intercellular communication. This Review reframes EVs by spatial distribution and function, distinguishing liquid-phase EVs, which disseminate through biofluids and enable systemic signalling, from matrix-bound EVs that are retained within the extracellular matrix and mediate localized, tissue-specific communication, evaluating their properties, functions and translational potential.