Hybrid Nonviral Nanocarriers Enable Functional Neural Modulation.

Abstract

Extracellular vesicles released from the neuronal cells mediate the transfer of proteins, nucleic acids, and neurotransmitter-related cargoes, shaping gene expression and intercellular communication across neural circuits. Leveraging this endogenous pathway, we fused astrocyte-derived exosomes with RNA-loaded synthetic liposomes to create sub-100 nm hybrid nanoparticles for central nervous system delivery. This design addresses key limitations of existing systems: conventional liposomes lack cell-type specificity and can be toxic, whereas native vesicles are difficult to load efficiently. By tuning a mildly cationic surface, the hybrids support efficient gene transfer to neurons without disrupting membrane integrity or inducing measurable cytotoxicity. We validated this platform in vivo by delivering Cre recombinase mRNA in transgenic mice and inducing channel rhodopsin-2 expression in the motor cortex and ventral tegmental area, yielding behavioral changes during optogenetic stimulation.