Systemic safety and immunophenotypic profiles of human adipose-derived mesenchymal stem cell exosomes: A comprehensive toxicological assessment

Exosome-based therapeutics derived from mesenchymal stem cells (MSCs) are emerging as promising candidates for regenerative medicine due to their potent immunomodulatory and regenerative effects and a favorable safety profile. In this study, safety was evaluated through general toxicity (4-week repeated-dose study including immunotoxicity), genotoxicity, and safety pharmacology studies of an exosome isolated from human adipose tissue-derived mesenchymal stem cells (ASC-Exosome) under OECD guidelines and GLP regulations. Toxicological assessments were performed at doses of 2 × 10 9 , 6 × 10 9 , and 2.0 × 10 10 particles/animal/day in a 4-week repeated-dose toxicity study via subcutaneous bolus injection to male and female mice 3 times weekly. In addition, the Ames test and in vitro and in vivo micronucleus tests were performed to assess genotoxic potential. To assess potential effects on major physiological systems, a series of standardized tests was carried out, including telemetry-based cardiovascular assessment, central nervous system (CNS) functional observational battery, respiratory function analysis, and cardiovascular system tests such as in vivo telemetry system and in vitro human ether-à-go-go-related gene (hERG) channel assay. General toxicity assessments revealed no adverse changes in clinical signs, body weight, hematology, clinical biochemistry, or macroscopic and histopathological findings. Immunophenotyping showed that alterations in lymphocyte and monocyte counts were attributable to redistribution and physiological uptake by the phagocyte system, respectively. Furthermore, ASC-Exosomes exhibited no mutagenic potential in either in vitro or in vivo genotoxicity tests and showed no adverse pharmacological effects in the safety pharmacology core battery. Taken together, these findings indicate that ASC-Exosomes were well tolerated under the conditions evaluated, with no adverse effects observed across a comprehensive battery of toxicological and pharmacological evaluations. These results establish a favorable safety profile for ASC-Exosomes, providing a robust non-clinical foundation for their advancement into clinical development.