{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:02:26Z","timestamp":1789718546416,"version":"4.0.1"},"reference-count":180,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2503602"],"award-info":[{"award-number":["2022YFC2503602"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>Liver fibrosis remains a major unmet clinical challenge characterized by persistent activation of hepatic stellate cells (HSCs), chronic inflammatory remodeling, and impaired hepatocyte regeneration. Although mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising cell-free therapeutics, native EVs are limited by insufficient target specificity, rapid systemic clearance, heterogeneous cargo composition, and poorly defined dose-response relationships, thereby constraining their translational potential. Recent advances in bioengineering have redefined MSC-EVs as programmable nanobiomaterial platforms rather than passive biological byproducts. Through multilevel engineering, including parent cell modification, cargo modulation, surface functionalization, and biomaterial-assisted delivery, MSC-EVs can be rationally designed to modulate key fibrogenic pathways, reprogram immune microenvironments, restore extracellular matrix homeostasis, and enhance hepatocyte regeneration. Concurrently, innovations in scalable three-dimensional bioprocessing, good manufacturing practice-compatible purification, and mechanism-linked potency assays are accelerating the transition of engineered EVs toward clinically viable products. This review integrates pathophysiological targeting with multilevel engineering strategies, with particular emphasis on nano-bio interface design, quality-by-design manufacturing, critical quality attribute definition, and key translational considerations, including dosing, safety, and regulatory frameworks. By positioning engineered MSC-EVs as precision biomaterial systems with controllable composition, programmable functionality, and tunable pharmacokinetics, we propose a rational design paradigm that bridges biological efficacy with scalable manufacturing and regulatory readiness. Collectively, such engineering integration is poised to transform EV-based antifibrotic therapy from experimental promise into clinically actionable intervention.<\/jats:p>","DOI":"10.3389\/fbioe.2026.1966076","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T07:13:39Z","timestamp":1789715619000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineered mesenchymal stem cell-derived extracellular vesicles as programmable biomaterial platforms for liver fibrosis: design principles, manufacturing and clinical translation"],"prefix":"10.3389","volume":"14","author":[{"given":"Fanghong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of General Surgery, The First Hospital of Lanzhou University","place":["Lanzhou, Gansu, China"]},{"name":"The First School of Clinical Medicine, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Hospital of Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoliang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Hospital of Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Hospital of Lanzhou University","place":["Lanzhou, Gansu, China"]},{"name":"Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongbin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Hospital of Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Hospital of Lanzhou University","place":["Lanzhou, Gansu, China"]},{"name":"The First School of Clinical Medicine, Lanzhou University","place":["Lanzhou, Gansu, China"]},{"name":"Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/nrd3978","article-title":"Extracellular vesicles: biology and emerging therapeutic opportunities","volume":"12","author":"Andaloussi","year":"2013","journal-title":"Nat. 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