Engineered mesenchymal stem cell-derived extracellular vesicles as programmable biomaterial platforms for liver fibrosis: design principles, manufacturing and clinical translation

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.