GiovenTUM 2025 - SIB

Bioinspired exosome-mimetic nanovesicles for targeted delivery of Coenzyme Q10: Coenzyme Q (CoQ) is an endogenous lipophilic quinone, ubiquitous in biological membranes, with antioxidant and bioenergetic properties. CoQ deficiency can result from either a genetic defect or secondary deficiencies due to aging, oxidative stress, or drug interaction with biosynthesis. In these conditions, CoQ supplementation represents a relevant strategy to mitigate CoQ deficit; however, numerous studies have demonstrated that the efficiency of dietary CoQ uptake is a limiting step. Exosomes and, more generally, extracellular vesicles (EVs), the endogenous nanocarriers capable of transferring biological information between cells, have recently been proposed as a new drug delivery system. EVs are similar to liposomes in size, shape, and structure. However, the ability of EVs to transport biomolecules to recipient cells due to surface receptors has made them attractive for drug delivery purposes. Here, we developed bioinspired exosome-mimetic nanovesicles to deliver ubiquinone (CoQ10) to different cell types. Briefly, myocytes were lysed, and their membrane protein fraction was isolated, mixed with a mixture of choline-based phospholipids and ubiquinone, and finally subjected to serial extrusion to obtain CoQ10-loaded synthetic nanovesicles (Q10-SVs). The Q10-SVs have a similar diameter, zeta potential, and surface phenotype to muscle-derived exosomes; furthermore, HPLC quantification data showed CoQ10 loading efficiencies between 40-60%. Human fibroblasts, Hela, mouse myoblasts (C2C12) and rat cardiomyocytes (H9C2) were treated with 5 μg/mL Q10-SVs for 24 hours to investigate the ability of SVs to deliver CoQ10 in a targeted manner. The quantification of CoQ10 in the target cells provides an exciting perspective, where C2C12 and H9C2 cells incubated with loaded SVs can take up more CoQ10 than other cell lines, and in general, engineered nanovesicles allowed a more efficient assimilation of CoQ10 compared to bare CoQ10-loaded liposomes. Finally, the antioxidant activity of the delivered CoQ10 was assessed using a wound-healing assay. In H9C2 and C2C12 cells pre-incubated with Q10-SVs and then treated with hydrogen peroxide, almost complete migration was observed after eighteen hours of recovery, significantly improved over free or liposome-delivered CoQ10, demonstrating that CoQ10 delivered by SVs is more bioavailable and can protect myocytes and cardiomyocytes against oxidative stress. In conclusion, these data suggest that synthetic nanovesicles decorated with membrane proteins may serve as novel exosome mimetics to deliver CoQ10 effectively.