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 <i>Clostridium butyricum</i> 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) <i>in vivo</i>, 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.