Modulation of the TGF-β/Smad Signaling Pathway by a Bioactive Oxidized Polygonati Rhizoma Polysaccharide Crosslinked Chitosan Hydrogel as Therapeutic Carrier for Parkinson's Disease Treatment.

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Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss compounded by oxidative stress and neuroinflammation within a self-perpetuating pathological brain microenvironment. Here, we report a bioactive injectable self-healing hydrogel (COPRP) constructed by crosslinking oxidized Polygonati rhizoma polysaccharide (OPRP) with carboxymethyl chitosan via dynamic Schiff base linkages. OPRP is structurally identified as an inulin neoseries-type fructan with relevance to TGF-β/Smad pathway regulation. Without levodopa loading, COPRP reduced ROS accumulation and M1-associated inflammatory markers in LPS-stimulated microglia. It also improved cell viability, preserved mitochondrial membrane potential, and maintained TH expression in 6-OHDA-challenged SH-SY5Y cells, supporting the intrinsic bioactivity of the hydrogel matrix. In a 6-OHDA rat PD model, COPRP significantly ameliorated motor deficits and preserved TH-positive neurons. Incorporating levodopa into COPRP creates a dual-mechanism platform combining active microenvironmental remodeling with passive dopaminergic supplementation. Proteomic analysis, corroborated by western blotting, identified the TGF-β/Smad signaling axis as the principal mechanistic mediator. Pharmacological intervention with pirfenidone attenuated TGF-β2/Smad2/3 activation and partially reduced the behavioral and neuroprotective effects associated with COPRP, supporting the functional involvement of this pathway. This work delineates how a defined polysaccharide structure modulates the intracranial pathological microenvironment, offering insights for the rational design of bioactive biomaterials targeting neurodegenerative disease.

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