Probiotic Spore-Based Oral Biotherapeutics Promote Brain Targeting toward Gut-Brain Dual-Regulation for Parkinson's Disease Treatment.

Traditional Parkinson's disease (PD) treatments primarily target the brain without addressing gut-derived influences. Probiotic spores not only mediate gut-brain communication but also offer potential for oral brain-targeted drug delivery, which holds significant value for gut-brain dual-regulation. In this work, probiotic spore-based oral biotherapeutics are developed for PD treatment. After oral administration, the spore systems cross the harsh gastrointestinal chemical barrier and germinate into Clostridium butyricum in the intestine to modulate the gut-brain axis. Simultaneously, the spore coat proteins shed from the surface of the spore could reassemble into drug-loaded nanosystems, which further enter Peyer's patch across intestinal microfold cells and then hitchhike on the macrophage to reach the brain for an anti-inflammatory effect. In terms of drug delivery, spore-based biotherapeutics utilize intestinal lymphatic drug transport to overcome multiple barriers (biochemical barrier, intestinal mucus barrier, enterocyte barrier, and blood-central nervous system barrier) in vivo, solving the overwhelming challenges of oral brain-targeted drug delivery. In terms of anti-PD efficacy, probiotic spores emphasize a comprehensive gut-brain dual-regulation technology, which is an alternative to traditional brain-targeted approaches with limited systemic regulatory capacity. Taken together, the probiotic spore-based live biotherapeutics possess high clinical translational value, providing insights into oral brain-targeted drug delivery and gut-brain dual-regulation in other central nervous system diseases.