Engineered extracellular vesicles with multitargeted anti-microRNA for diabetes-induced cognitive impairment therapy

RNA therapeutics have shown considerable promise in the treatment of various neurological disorders, while their effective delivery across the blood-brain barrier (BBB) and modulation of multiple microRNA pathological targets remains critical challenges. In this study, we developed a dual-engineered extracellular vesicle (EV) system for the target delivery of multiple microRNA inhibitors (anti-miRs) to the brain to treat diabetes-induced cognitive impairment. The engineered EVs were efficiently loaded with a panel of therapeutic anti-miRs and demonstrated effective synaptic recovery in primary neurons under synapse-losing conditions. In vivo, the system showed enhanced brain accumulation after intravenous injection. Furthermore, in a diabetic mouse model, treatment with this system significantly restored brain-derived neurotrophic factor (BDNF) and synaptic markers levels, leading to marked improvement in cognitive deficits. These findings underscore the potential of this EV-based platform as a brain-targeted strategy for microRNA-based therapeutics in neurodegenerative and metabolic central nervous system disorders.