Mesenchymal stromal cell–derived extracellular vesicles in regenerative medicine: Standardisation, bioengineering and clinical translation
Yusuke Shimizu, Yoshikazu Inoue, Naoki Matsuura, Tatsuya Ishii, Yoshihiro Sowa, Hiroshi Sunami, Edward Hosea Ntege
Abstract
Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have emerged as promising cell-free therapeutics that recapitulate key paracrine functions of MSCs whilst mitigating limitations of viable-cell therapies. Clinical translation is hindered by inconsistent dose metrics, lack of validated potency assays, and manufacturing complexities. Here we review advances in MSC-EV standardisation, source and culture determinants, engineering and delivery platforms, and clinical applications, exemplified by chronic wound healing. We operationalise dual-metric dosing (particles plus protein) linked to mechanism-aligned potency assays, adopt a route-aware exposure–response framework to guide delivery strategies, and propose decision matrices aligning MSC sources and bioprocesses with indication-specific tasks. Good Laboratory Practice safety panels and Good Manufacturing Practice scale-up strategies are outlined to support regulatory readiness. Early clinical studies demonstrate feasibility and short-term safety but reveal heterogeneous efficacy, underscoring the need for harmonised dosing and potency measures. Collectively, these insights provide a roadmap to advance MSC-EVs as indication-matched regenerative medicines. • Dual-metric dosing (particles plus protein) with MOA-linked potency assays. • Route-aware exposure-response guides delivery choice and depot design. • Decision matrix aligns MSC source, conditioning and process to indication. • GLP safety panels and comparability triggers for process changes. • GMP-aligned scale-up (TFF/HFB) integrated with release-level QC and stability.