Embryonic cortical extracellular vesicles confer neuroprotection via multipathway signaling with CaMKIIα as a key mediator

Extracellular vesicles (EVs) are increasingly recognized for their roles in orchestrating embryonic development. Emerging preclinical evidence further suggests that EVs from young organisms possess innate regenerative potential for adult or injured tissues. Here we show that small extracellular vesicles (sEVs) isolated from the mouse embryonic cortex exert neuroprotective effects in vitro and in vivo. Proteomic profiling revealed that embryonic sEVs are enriched with effectors of receptor tyrosine kinase activation, anti-inflammatory responses, and protein synthesis. Notably, we identified BDNF as a surface-bound cargo on embryonic sEVs, displaying superior stability and receptor activation kinetics than its non-vesicular form. Phospho-proteomic analysis further revealed that sEVmediated neuroprotection is driven primarily by the CaMKII signaling axis, which targets downstream effectors of microtubule stability, synaptic plasticity, and membrane-cytoskeleton interactions. Critically, embryonic sEVs, but not those from aged mice, restored microtubule stability and mitochondrial respiration in aged neurons in vitro. Our findings identify embryonic cortical sEVs as significant regulators of neuronal resilience and provide a molecular blueprint for EV-based strategies in neurodegeneration and aging research.