Probiotic Spore Inspired Oral Drug Delivery System With Multiple-Barriers-Crossing Ability Modulates Gut-Brain Axis for Parkinson's Disease Therapy.

For Parkinson's disease (PD), the development of oral brain-targeted drug delivery is challenging due to various physiological barriers. Besides the brain, the effect of the gut on the microbiome-gut-brain axis should not be ignored. Therefore, developing a gut-brain dual-targeted delivery system with multiple-barriers-crossing ability is meaningful. During the germination of probiotic spores, we find that spore coat proteins (SP) shed from their surface possess excellent characteristics (re-assembling into nanoparticles, multiple-barriers penetration ability, antioxidant property, etc.), offering potential for brain-targeted drug delivery. Inspired by this, we propose a probiotic spore based oral drug delivery system to dual-regulate the gut-brain. After oral administration, the spore system crosses the harsh gastrointestinal chemical barrier. Spores germinate in the intestine into probiotics to modulate the gut-brain axis. Meanwhile, the SP-derived reassembled nanosystems cross multiple barriers (intestinal mucus barrier, enterocyte barrier, blood-brain barrier) to reach brain and further reduce oxidative stress. Notably, neurodegeneration and behavioral deficits are alleviated in PD mice. Such gut-brain dual-regulation strategy emphasizes a comprehensive and promising technique for central nervous system disease treatment, which may be an alternative to traditional single-targeted methods. Furthermore, the probiotic spore-based oral biotherapeutics with multiple-barriers-crossing efficiency provide new insight into other brain diseases.