ABSTRACT: Rationale: Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement, muscle control, and balance. Effective therapeutic options for this condition are limited. Natural therapies, including lifestyle changes, probiotics, and muscle relaxants, have received attention for symptomatic relief. Colostrum, particularly its extracellular vesicles (C-EVs), has emerged as a promising nutraceutical with the potential to improve therapeutic outcomes in divergent diseases. Methods: We purified and characterized (C-EVs) as a putative cell-based therapy. Theranostic (biodistribution, diagnostic, and therapeutic) efficacy studies were performed in C-EV-treated mice intoxicated with methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The C-EV tissue distribution, anti-inflammatory and neurorestorative activities were examined. These include transcriptomic, immune, and neuroprotective profiles linked to disease outcomes. Results: C-EV-treated MPTP mice showed reduced microglial activation and restored neuronal responses. RNA sequencing and transcriptomic analyses have demonstrated reduced immune cell recruitment and activation in the disease-affected brain subregions. The activation of canonical inflammasomes, pro-inflammatory cytokines, and chemokine expression was controlled. C-EV treatment reduced the levels of disease-associated immune-regulatory transcription factors. Simultaneously, Treg-associated adaptive immune responses increased. Multiple C-EV-miR-isolated immune regulatory cargos are linked to neuroinflammation and nigral preservation. C-EVs loaded with miR-20a-5p, miR-23b-3p, let-7a-5p, miR-22-3p, and miR-30a-3p mimics attenuated pro-inflammatory cytokines in activated microglia. Conclusions: C-EVs elicit neuroprotective responses in MPTP-intoxicated mice. These responses control microglial activation and facilitate neuroprotective responses.
