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.

Mesenchymal stem cells (MSCs) are identified as promising candidates for reversing liver fibrosis benefiting from their excellent properties in tissue repair and immune regulation, while their therapeutic efficacy still requires improvement. Herein, we develop novel multiple engineered MSCs with precise targeting capability and highly expressed growth factors by integrating membrane modification and genetic engineering technology for effective liver fibrosis treatment. These MSCs are imparted with liver-targeting ability via coating their membranes with heparin-lipid conjugates. By utilizing genetic engineering technology to input two designed circular RNA formulations, the MSCs were also imparted with significantly enhanced expression levels and duration of antifibrotic growth factors. Through mouse models of liver fibrosis, we have demonstrated that a single dose of the resultant engineered MSCs can restore liver function by regulating the expression of relevant genes and degrading the extracellular matrix. These promising therapeutic outcomes highlight the significant potential of the engineered MSCs in alleviating liver fibrosis.