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Conventionally, EVs are cryopreserved at ultra\u2010low temperatures, with substantial cryoinjury associated with the freeze\/thaw cycle. Lyophilization has emerged as a promising alternative approach; however, suboptimal outcomes remain owing to the challenge of lyoprotectant delivery into EVs. Here, the atypical transport property of the EV membrane is unraveled, and lyoprotective trehalose is delivered into EVs by combining substantial hypotonicity (below intravesicular colloid osmolality) and mild heat shock (42\u00a0\u00b0C). Consequently, the lyophilization of trehalose\u2010laden EVs is notably enhanced, with less EV loss, more RNA and protein retention, and superior therapeutic efficacy. Moreover, the EVs can be co\u2010reconstituted and co\u2010lyophilized with hyaluronic and methylcellulose (HAMC) hydrogel carriers, yielding excellent preservation outcomes and controlled EV release. Lyophilized EVs or HAMC\u2010EVs maintain Treg cell regulation in vitro and experimental autoimmune encephalomyelitis disease treatment in vivo. Overall, not only are EVs and EV\u2013hydrogel constructs efficiently lyophilized for widespread application, but a thermodynamic approach is also developed to safely and uniformly deliver various hydrophilic molecules into EVs.<\/jats:p>","DOI":"10.1002\/adhm.202500522","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T17:37:45Z","timestamp":1759772265000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Thermodynamic Delivery of Trehalose into Extracellular Vesicles for Enhanced Lyophilization"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9024-3265","authenticated-orcid":false,"given":"Tian","family":"Wang","sequence":"first","affiliation":[{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 P. R. 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