Metabolic programming promotes cellular uptake of extracellular vesicles and boosts in vivo therapeutic efficacy

Extracellular vesicles (EVs) are promising carriers for delivering therapeutic cargos to target cells, yet their in vivo delivery efficacy remains limited despite extensive efforts to optimize their physical and chemical properties. Recognizing that EV uptake is an interactive process between EVs and cells, we hypothesized that modulating cell states could enhance the uptake and therapeutic impact of drug-loaded EVs. In this study, we investigated how the cellular metabolome influences EV uptake in neuroblastoma cells. Our results demonstrate that EV uptake varies significantly depending on the cells' metabolic conditions. Through multi-omic analyses, we identified a metabolite cocktail composed of pyruvate and methionine that enhances EV uptake by 150%. In an animal cancer model, co-administration of these metabolite adjuvants markedly reduced tumor size. This work highlights the potential of targeting the cellular metabolome to optimize drug delivery and introduces a straightforward adjuvant strategy to enhance nanoparticle delivery efficacy.