Biodistribution of Intratracheal, Intranasal, and Intravenous Injections of Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles in a Mouse Model for Drug Delivery Studies

Abstract

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are extensively studied as therapeutic tools. Evaluation of their biodistribution is fundamental to understanding MSC-EVs’ impact on target organs. In our work, MSC-EVs were initially labeled with DiR, a fluorescent lipophilic dye, and administered to BALB/c mice (2.00 × 1010 EV/mice) through the following routes: intravenous (IV), intratracheal (IT) and intranasal (IN). DiR-labeled MSC-EVs were monitored immediately after injection, and after 3 and 24 hours (h). Whole-body analysis, 3 h after IV injection, showed an accumulation of MSC-EVs in the mice abdominal region, compared to IT and IN, where EVs mainly localized at the levels of the chest and brain region, respectively. After 24 h, EV-injected mice retained a stronger positivity in the same regions identified after 3 h from injection. The analyses of isolated organs confirmed the accumulation of EVs in the spleen and liver after IV administration. Twenty-four hours after the IT injection of MSC-EVs, a stronger positivity was detected selectively in the isolated lungs, while for IN, the signal was confined to the brain. In conclusion, these results show that local administration of EVs can increase their concentration in selective organs, limiting their systemic biodistribution and possibly the extra-organ effects. Biodistribution studies can help in the selection of the most appropriate way of administration of MSC-EVs for the treatment of different diseases.

Adjunctive treatment of sepsis with mesenchymal stem cell-derived extracellular vesicles: a systemic review and meta-analysis of pre-clinical studies

“…Although immune regulation and differentiation capabilities of MSCs are bene cial for immune modulation and repair in sepsis, several limitations of cell therapy, including uncontrolled cell proliferation, malignant cell differentiation, and low engraftment (9), are mentioned. Here, there are two included studies comparing the effectiveness between MSC cell-based therapy and MSC-EVs on sepsis that demonstrated the greater e cacy of MSC-EVs, possibly through the better biodistribution of MSC-EVs throughout the body and tissue-speci c localization (10), or alternatively via secondary effects on activated host cells in tissue upon EV uptake (30). Due to the larger sizes of MSCs than MSC-EVs, the distribution of MSCs after intravenous injection is limited to some organs (livers and lungs) (31), while MSC-EVs rapidly spread throughout the whole body and might also be delivered through the EV-uptake cells.…”

Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury

“…However, systemic dilution presents a significant challenge with this approach, as most exosomes transplanted intravenously accumulate in the liver, lung, and spleen, resulting in only approximately 0.00–0.01% reaching the brain [ 9 ]. Consequently, intranasal administration is increasingly recognized as a promising therapeutic route for delivery [ 38 , 39 ]. The method has been reported to be superior to intravenous transplantation, as none of the transplanted exosomes are found in the brain 24 h after intravenous transplantation.…”

Bioengineering extracellular vesicle cargo for optimal therapeutic efficiency

“…were administered a four times higher dose of EVs than the intranasal group. 153 Twenty-four hours after administration, the greatest accumulation of EVs was in the liver, lungs, and spleen of i.v.-treated mice, with some accumulation in the heart, kidney, and brain. In contrast, relatively high accumulation of EVs was noted in the brain of mice treated intranasally, with relatively low levels in the heart and gut.…”