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

ABSTRACT 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.