Optimizing dose and delivery route in mesenchymal stromal cells (MSCs)-based therapy: A systematic review of their...

Mesenchymal stromal cell (MSC)-based therapies have demonstrated broad therapeutic potential across inflammatory, degenerative, and neurological disorders; however, clinical outcomes remain highly variable, largely due to heterogeneity in cell source, dosing strategies, routes of administration, treatment timing, and patient-specific factors. This review evaluates how MSC dose and delivery route influence clinical efficacy and safety, and whether specific administration routes require tailored dosing strategies. A systematic literature search of PubMed, Scopus, Web of Science, and the Cochrane Library (2015-2025) identified 29 eligible clinical trials employing intravenous (n = 13), intrathecal (n = 10), intramuscular (n = 4), intranasal (n = 1), and multi-route (n = 1) administration, with doses ranging from 2 × 10⁵ cells/kg body weight to fixed doses exceeding 1 × 10⁸ cells. Intravenous delivery was predominantly used for systemic indications but was limited by pulmonary first-pass sequestration, whereas intrathecal and intranasal routes enhanced central nervous system targeting and intramuscular administration supported prolonged local persistence and paracrine activity. Although MSC therapy was generally well tolerated across studies, substantial outcome variability underscores the need for harmonized frameworks for dose selection, route optimization, and manufacturing consistency. This review highlights critical gaps in dose-route optimization and supports the development of standardized clinical guidelines and advanced strategies, including MSC priming and engineering, to improve therapeutic predictability and translational success.