A Hydrogel-Mediated Sustained-Release Platform Alters the Biodistribution of Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in Mice

Mesenchymal stem cell-derived exosomes represent a promising therapeutic avenue for tissue regeneration, yet their clinical translation is hindered by rapid clearance following systemic administration and the lack of optimized, sustained-release delivery strategies. To address these challenges, we crafted a biomimetic hydrogel to carry and gently release MSC-derived exosomes. We engineered a biocompatible, dextran-based composite hydrogel (carboxymethyl chitosan-oxidized dextran/tannic acid-iron complex, CMC-OD/TA-Fe(III)) for the encapsulation and sustained release of human umbilical cord MSC-derived exosomes. We systematically compared the organ biodistribution of exosomes delivered via this hydrogel platform using three distinct local routes: intraperitoneal injection, oral (intragastric) administration, and rectal administration, employing in vivo imaging and tissue immunofluorescence analyses in C57BL/6J mice. Following a single intraperitoneal dose, released exosomes accumulated primarily in the liver and spleen, with minimal brain enrichment. Notably, both oral and rectal administration—non-invasive alternatives to injection—facilitated considerable exosome dissemination to multiple organs. The significant distribution observed via the oral route specifically challenges the prevailing assumption regarding the inefficacy of gastrointestinal delivery for exosome-based therapeutics. This study provides critical insights into administration-route-dependent biodistribution patterns and proposes novel, non-invasive delivery strategies to enhance the therapeutic efficacy and application scenarios of exosomes.