Gastrointestinal In Situ Self‐Assembled Gastrodia Elata Polysaccharide Hydrogel Enables Parkinson's Disease Therapy via Gut‐Brain Axis Modulation

Parkinson's disease (PD) is closely associated with abnormal α-synuclein propagation along the gut-brain axis and progressive dopaminergic neuronal loss. Traditional oral preparations suffer from weak gastrointestinal resistance, rapid degradation and poor gut-brain axis regulation. Here, we constructed a gastrodia elata polysaccharide-functionalized dual-network GEPH hydrogel via thiol-maleimide click crosslinking. GEPH possesses favorable biocompatibility, regular porous microstructure and tailored rheological properties suitable for gastrointestinal delivery, showing outstanding erosion resistance and structural stability in simulated intestinal fluid. It achieves in situ gelation in the gastrointestinal tract and maintains 24 h long-term retention after oral administration. GEPH modulates gut microbiota composition and metabolite profiles, repairs intestinal barrier and neuronal injury in PD mice such as Corynebacterium, CAG_95, and Akkermansia, while regulated metabolite abundance such as 3-methyl-4-cis-hydroxy-2-butenal, Nicotinic acid, Linolenate. By regulating the TLR4/NF-κB pathway and gut-brain axis, it inhibits abnormal aggregation and spread of intestinal and cerebral α-synuclein, alleviates neuroinflammation and neuronal apoptosis, protects dopaminergic neurons and ameliorates motor dysfunction. This study proposes GEPH as a new type of oral functionalized dual-network hydrogel formulation that regulates the gut-brain axis, promoting the clinical application of a new strategy for oral drug administration for gastrointestinal prevention and treatment of PD.