Screening extracellular vesicle-producing cells enables delivery of silencing RNAs to the kidney and brain in small and large animals

Small extracellular vesicles (sEVs) can transport RNA between cells. Investigations of sEVs as delivery vehicles for RNA therapeutics have frequently used sEVs from HEK293 cells. Here, we screened different cell sources of sEVs for small interfering RNA (siRNA) delivery to kidney glomeruli after intravenous injection and the brain after direct injection into the central nervous system. Although sEVs derived from various cell lines failed to effectively deliver siRNA to these tissues, we identified specific cells whose sEVs successfully delivered siRNA to the kidney glomeruli or the brain to reduce pathology in models of apolipoprotein L1 ( APOL1 )-mediated kidney disease and Tau -mediated neurodegeneration, among others. sEV delivery vehicles required doses of siRNA substantially lower than those of current delivery vehicles and scaled with body mass to the rabbit kidney and non-human primate brain. Identifying optimal cell sources of sEVs enables low-dose, scalable, and selective siRNA delivery to extrahepatic tissues and cell types.