Neuroprotective Effects of Salvia Miltiorrhiza-Derived Extracellular Nanovesicles in Traumatic Brain Injury

Traumatic brain injury (TBI) initiates a series of pathogenic processes, including neuroinflammation, oxidative stress, and metabolic failure, that ultimately result in neurological damage. Plant-derived bioactive compounds have demonstrated promise as treatments to reduce TBI-associated neurodegeneration. However, most previous studies have investigated the efficacy of a single active ingredient, and many such compounds have poor permeability across the blood-brain barrier (BBB), limiting their therapeutic potential. Cells release vesicles containing various signaling factors, ions, and nutrients that are subsequently taken up by adjacent cells via endocytosis. The present study explored the therapeutic effects of extracellular vesicles derived from Salvia miltiorrhiza-derived extracellular vesicles (SalEVs) for the treatment of TBI in mice model via biochemical, histological, microfluorometric, behavioral, and omics analyses. Isolated SalEVs contain an array of bioactive compounds, including tanshinones and salvianolic acids, encapsulated within a unique bilayer lipid structure, as revealed by electron microscopy and chromatography. Membrane labeling indicated that these SalEVs readily crossed the BBB of TBI model mice and accumulated at the injury site. Systemic administration of SalEVs to TBI model mice suppressed microglial activation, infiltration at the injury site, and proinflammatory phenotype transition as well as astroglial activation, neuronal reactive oxygen species accumulation, and apoptotic neuronal cell death. In addition, SalEVs preserved the dendritic structure following TBI. Omics revealed changes in gene and metabolite expression consistent with these anti-inflammatory, antioxidant, and neuroprotective effects. Behavioral tests also revealed partial rescue of TBI-induced spatial memory deficits. Systemic SalEV administration may be an effective therapeutic strategy for TBI by simultaneously targeting multiple pathogenic pathways.