Efficient penetration of deformable exosomes via the nose-to-brain pathway and carnosine-dependent remodeling of the acidic neuronal microenvironment to potentiate antidepressant efficacy

The pathogenesis of depression is closely associated with neuronal mitophagy dysfunction and dysregulated energy metabolism. The acidic intracellular microenvironment of depressed neurons is increasingly recognized as a pivotal driver of depressive-like behaviors. Nevertheless, therapeutic strategies for this pathological feature remain largely underexplored. Meanwhile, the nasal mucosal barrier constitutes a major bottleneck for nose-to-brain drug delivery in depression treatment. Constructing carriers with superior deformability can enhance mucosal penetration and the efficiency of intracerebral delivery. Herein, an exosome (EXO)-based nanoengineered platform via conjugation of carnosine (CAR) and rabies virus glycoprotein 29 (RVG29) peptide loaded with miR-532-5p (RVG/CAR–EXOm–miR) was designed. Specifically, the elevated cholesterol content of 130% in RVG/CAR–EXOm–miR markedly reinforced the deformability of engineered exosomes and the nasal mucosal penetration, thereby improving brain delivery efficiency. Subsequently, the entire system migrated to brain neurons due to the distinct neuronal targeting capability of RVG29. Upon internalization into neurons, CAR exerted a pH-regulating function to buffer the intracellular acidic microenvironment, rescuing the impairment of synaptic plasticity and offering supportive therapeutic effects against depression. Meanwhile, miR-532-5p restored mitochondrial function. These findings demonstrate that RVG/CAR–EXOm holds great potential as an efficient nose-to-brain drug delivery system for depression therapy.