Engineering Modifications of Mesenchymal Stem Cell-Derived Extracellular Vesicles to Prolong Systemic Circulation, Evade Mononuclear Phagocyte System Clearance, and Enhance Targeted Delivery to the Injured Spinal Cord Following Intravenous Administration in Rodent Models of Spinal Cord Injury: A Systematic Review

This project is a preclinical systematic review that aims to evaluate engineering modifications of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) designed to improve their systemic pharmacokinetics and therapeutic efficacy following intravenous administration in rodent models of spinal cord injury (SCI). The review will focus on engineering strategies intended to prolong circulation time, reduce clearance by the mononuclear phagocyte system (MPS), enhance biodistribution and targeting to injured spinal cord tissue, and improve neurological recovery. The review will include controlled animal studies involving rats or mice with traumatic SCI that investigate engineered MSC-EVs administered intravenously. Primary outcomes will include pharmacokinetic parameters, biodistribution, and spinal cord targeting efficiency. Secondary outcomes will include functional recovery, histopathological findings, neuroinflammation, tissue repair, molecular mechanisms, and safety. The protocol follows the PRISMA-P 2015 guidelines for systematic review protocols and will be conducted and reported in accordance with PRISMA 2020 recommendations. Risk of bias will be assessed using the SYRCLE Risk of Bias tool for animal intervention studies. This review aims to identify the most promising engineering strategies for enhancing MSC-EV delivery to the injured spinal cord and to provide evidence that may facilitate the clinical translation of engineered extracellular vesicle therapies for spinal cord injury.