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Nonetheless, in acute liver failure (ALF), particularly when the ingestion is substantial, NAC may not fully restore liver function. NAC administration in ALF has limitations and potential adverse effects, including nausea, vomiting, diarrhoea, flatus, gastroesophageal reflux, and anaphylactoid reactions. Mesenchymal stromal cell (MSC)\u2010based therapies using paracrine activity show promise for treating ALF, with preclinical studies demonstrating improvement. Recently, MSC\u2010derived extracellular vesicles (EVs) have emerged as a new therapeutic option for liver injury. MSC\u2010derived EVs can contain various therapeutic cargos depending on the cell of origin, participate in physiological processes, and respond to abnormalities. However, most therapeutic EVs lack a distinct orientation upon entering the body, resulting in a lack of targeting specificity. Therefore, enhancing the precision of natural EV delivery systems is urgently needed. Thus, we developed an advanced targeting technique to deliver modified EVs within the body. Our strategy aims to employ bioorthogonal click chemistry to attach a targeting molecule to the surface of small extracellular vesicles (sEVs), creating exogenous chimeric antigen receptor\u2010modified sEVs (CAR\u2010sEVs) for the treatment. First, we engineered azido\u2010modified sEVs (N<jats:sub>3<\/jats:sub>\u2010sEVs) through metabolic glycoengineering by treating MSCs with the azide\u2010containing monosaccharide N\u2010azidoacetyl\u2010mannosamine (Ac4ManNAz). Next, we conjugated N<jats:sub>3<\/jats:sub>\u2010sEVs with a dibenzocyclooctyne (DBCO)\u2010tagged single\u2010chain variable fragment (DBCO\u2010scFv) that targets the asialoglycoprotein receptor (ASGR1), thus producing CAR\u2010sEVs for precise liver targeting. The efficacy of CAR\u2010sEV therapy in ALF models by targeting ASGR1 was validated. MSC\u2010derived CAR\u2010sEVs reduced serum liver enzymes, mitigated liver damage, and promoted hepatocyte proliferation in APAP\u2010induced injury. Overall, CAR\u2010sEVs exhibited enhanced hepatocyte specificity and efficacy in ameliorating liver injury, highlighting the significant advancements achievable with cell\u2010free targeted therapy.<\/jats:p>","DOI":"10.1002\/jev2.70044","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T02:54:15Z","timestamp":1738637655000},"source":"Crossref","is-referenced-by-count":33,"title":["Small Extracellular Vesicles Engineered Using Click Chemistry to Express Chimeric Antigen Receptors Show Enhanced Efficacy in Acute Liver Failure"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5708-6066","authenticated-orcid":false,"given":"Yen\u2010Ting","family":"Lu","sequence":"first","affiliation":[{"name":"Graduate Institute of Pharmacology National Taiwan University College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2575-969X","authenticated-orcid":false,"given":"Tzu\u2010Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Pharmacology National Taiwan University College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8327-6835","authenticated-orcid":false,"given":"Hsin\u2010Hung","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Pharmacology National Taiwan University College of Medicine  Taipei Taiwan"},{"name":"MediDiamond Inc.  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