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Despite their potential, the mechanisms underlying EV release, uptake and distribution remain unclear. Here, we leverage high\u2010resolution live\u2010cell imaging, quantitative analytical methods and in vivo mouse models to define the major determinants of EV diffusion. Our findings reveal that cell density plays a crucial role in EV dissemination. Specifically, sparsely distributed cells exhibit higher EV release rates into the supernatant due to increased surface exposure in vitro. In contrast, densely packed cells promote EV internalization and degradation by adjacent cells, effectively restricting EV diffusion in vivo and in vitro. As a result, EVs travel only limited distances, with the majority being internalized by adjacent cells. These findings challenge the prevailing assumption that any EV can act as long\u2010range messengers and instead highlight their function as short\u2010range communication agents primarily confined within their tissue or organ of origin. This study provides fundamental insights into EV\u2010mediated intercellular signalling and has important implications for their use in diagnostic and therapeutic applications.<\/jats:p>","DOI":"10.1002\/jev2.70169","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:02:04Z","timestamp":1761894124000},"source":"Crossref","is-referenced-by-count":12,"title":["Exploring the Spatial Limits of Extracellular Vesicles\u2010Mediated Intercellular Communication"],"prefix":"10.1002","volume":"14","author":[{"given":"Federico","family":"Colombo","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy The Ohio State University Columbus Ohio USA"},{"name":"Comprehensive Cancer Center The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kartik","family":"Nimkar","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, 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