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Besides the brain, the effect of the gut on the microbiome\u2010gut\u2010brain axis should not be ignored. Therefore, developing a gut\u2010brain dual\u2010targeted delivery system with multiple\u2010barriers\u2010crossing ability is meaningful. During the germination of probiotic spores, we find that spore coat proteins (SP) shed from their surface possess excellent characteristics (re\u2010assembling into nanoparticles, multiple\u2010barriers penetration ability, antioxidant property, etc.), offering potential for brain\u2010targeted drug delivery. Inspired by this, we propose a probiotic spore based oral drug delivery system to dual\u2010regulate the gut\u2010brain. After oral administration, the spore system crosses the\u00a0harsh gastrointestinal chemical barrier. Spores germinate in the intestine into probiotics to modulate the gut\u2010brain axis. Meanwhile, the SP\u2010derived reassembled nanosystems cross multiple barriers (intestinal mucus barrier, enterocyte barrier, blood\u2010brain barrier) to reach brain and further reduce oxidative stress. Notably, neurodegeneration and behavioral deficits are alleviated in PD mice. Such gut\u2010brain dual\u2010regulation strategy emphasizes a comprehensive and promising technique for central nervous system disease treatment, which may be an alternative to traditional single\u2010targeted methods. Furthermore, the probiotic spore\u2010based oral biotherapeutics with multiple\u2010barriers\u2010crossing efficiency provide new insight into other brain diseases.<\/jats:p>","DOI":"10.1002\/exp2.70221","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:49:06Z","timestamp":1788943746000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Probiotic Spore Inspired Oral Drug Delivery System With Multiple\u2010Barriers\u2010Crossing Ability Modulates Gut\u2010Brain Axis for Parkinson's Disease Therapy"],"prefix":"10.1002","volume":"6","author":[{"given":"Qianhua","family":"Feng","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences State Key Laboratory of Antiviral Drugs Pingyuan Laboratory Zhengzhou University  Zhengzhou China"},{"name":"Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases  Zhengzhou China"},{"name":"Hubei Provincial 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