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.