Ancient Herbal Polysaccharide Turned Self-Healing Brain Gel Shows Promise Against Parkinson’s Disease

A hydrogel built from an oxidized polysaccharide extracted from the rhizome of Polygonatum sibiricum, a plant long used in traditional Chinese medicine as the herb known as Huangjing, has shown striking therapeutic effects in rat and cellular models of Parkinson’s disease. Reporting in Advanced Science, a research team led by investigators at Ningbo University and Wenzhou Medical University describes an injectable, self-healing material that does far more than ferry drugs into the brain. The gel itself, they show, actively rewires the pathological environment of the damaged substantia nigra by engaging the TGF-β/Smad signaling pathway, a mechanism the authors substantiated with proteomics, western blotting, and a pharmacological intervention using the TGF-β attenuator pirfenidone.

The story begins with a chemical problem. Polygonati rhizoma polysaccharide, or PRP, is the most abundant bioactive component of Huangjing and has previously been shown to reduce dopaminergic neuron loss, suppress oxidative stress, and temper microglial inflammation in models of Parkinson’s disease. But PRP is built mostly of glucose and fructose monosaccharides whose abundant hydroxyl groups form strong intramolecular hydrogen bonds. That makes the molecule poorly reactive in water and difficult to combine with drugs or biomaterials, limiting its use in drug delivery or tissue engineering. To unlock its potential, the team turned to controlled periodate oxidation, a strategy widely used to convert the vicinal diols of polysaccharides such as dextran, alginate, and hyaluronic acid into reactive aldehyde groups.

Treating PRP with sodium periodate yielded oxidized PRP, or OPRP, with a degree of oxidation of roughly 16.33 percent. Structural elucidation was exhaustive: proton and carbon NMR, two-dimensional NMR experiments including COSY, HSQC, HMBC, and NOESY, FTIR spectroscopy, methylation analysis, and monosaccharide composition together identified OPRP as an inulin neoseries-type fructan with a weight-average molecular weight of 4.6 kilodaltons. Fructose made up more than 93 percent of the monosaccharide content, the backbone was dominated by 1,2-linked fructose residues exceeding 55 percent, and a low dispersity ratio of 1.04 confirmed the purity of the isolated polysaccharide. FTIR revealed the characteristic carbonyl absorption at 1730 per centimeter, while furanose-specific peaks at 1016, 1115, 939, and 816 per centimeter confirmed the β-D-furanose fructose architecture.

With reactive aldehydes in hand, the researchers crosslinked OPRP with carboxymethyl chitosan through Schiff base reactions, the reversible condensation between aldehyde and amino groups that underlies many self-healing injectable hydrogels. The optimized formulation, containing 2.5 percent OPRP and 5 percent carboxymethyl chitosan, gelled within ten minutes and displayed a storage modulus of about 230 pascals, a stiffness squarely within the soft 0.1 to 1 kilopascal range considered favorable for neural tissue. Scanning electron microscopy revealed a uniform porous network with an average pore diameter near 45.4 micrometers and porosity of roughly 95.4 percent. Rheological testing showed the gel could withstand strains up to 370 percent before yielding, then fully recover its modulus after repeated damage-healing cycles. It flowed smoothly through a 30-gauge needle fine enough to write letters, and degraded slowly in saline, retaining about 34 percent of its mass after fourteen days.

The material’s drug delivery credentials were demonstrated with Fast Green FCF, a hydrophilic stand-in for levodopa, which diffused steadily from the gel over a fourteen-day dialysis experiment before reaching a plateau around day ten. But the more provocative finding concerns what the gel does without any drug at all. In free radical scavenging assays, drug-free COPRP clearly outperformed a bioinert control hydrogel made from carboxymethyl chitosan and a dibenzaldehyde-terminated polyethylene glycol crosslinker, and adding levodopa more than doubled the scavenging capacity, an effect attributed to the polyphenolic chemistry of the drug itself. The authors are careful to frame the levodopa-loaded version, COPRPL, not as a simple carrier-drug relationship but as a deliberate dual-mechanism design in which the OPRP backbone remodels the diseased brain microenvironment while levodopa replenishes dopaminergic signaling.

In cellular experiments, the team challenged BV2 microglia with lipopolysaccharide to provoke inflammation and reactive oxygen species. Hydrogels containing OPRP significantly reduced ROS fluorescence, cut the M1-type pro-inflammatory markers IL-1β, iNOS, and TNF-α by more than 40 percent, and raised the M2-type anti-inflammatory marker CD206 by over 1.8-fold, with the levodopa-loaded gel pushing that upregulation past threefold. In a human neuroblastoma SH-SY5Y model of Parkinsonian injury induced by 6-hydroxydopamine, COPRP restored cell viability, reduced early and late apoptosis, rescued mitochondrial membrane potential as measured by JC-1 staining, and preserved expression of tyrosine hydroxylase, the rate-limiting enzyme of dopamine synthesis. The bioinert control gel did none of this, isolating the benefit to the OPRP component.

The in vivo results were the most consequential. The researchers lesioned the medial forebrain bundle of Sprague Dawley rats with 6-hydroxydopamine, confirmed successful Parkinsonian induction in about 94 percent of animals by apomorphine-evoked rotation, then injected four microliters of saline, inert hydrogel, COPRP, or COPRPL stereotaxically into the lesion site. By day seven, COPRP-treated rats were already rotating significantly slower than controls, and by day fourteen their circling speed had fallen to roughly 8.2 seconds per round. In the cylinder test, forelimb contact rates on the impaired side recovered by more than 15 percent in OPRP-gel groups and over 22 percent with levodopa loading, while open-field testing showed increased locomotion and exploration. Histology confirmed the pattern: more tyrosine hydroxylase-positive dopaminergic neurons survived in the substantia nigra, activated Iba1-positive microglia and GFAP-positive astrocytes were markedly reduced, and cerebral superoxide dismutase activity rose to approximately 53 units per milligram of tissue in the levodopa-loaded group.

To find the mechanism, the team compared brain proteomes of inert-hydrogel and COPRP-treated rats using data-independent acquisition mass spectrometry on a timsTOF HT platform. Principal component analysis cleanly separated the groups, and differential expression identified 161 upregulated and 38 downregulated proteins. KEGG enrichment pointed to focal adhesion, sphingolipid signaling, axon guidance, Rap1 signaling, and neurotrophin pathways, with selective remodeling of extracellular matrix components such as the Col6a collagens, paxillin, and talin. Critically, gene set enrichment analysis confirmed significant upregulation of the entire TGF-β signaling pathway. Western blotting then verified that COPRP increased TGF-β1 and TGF-β2 protein abundance, raised total Smad2/3, and markedly enhanced its phosphorylated form, the signature of pathway activation. Unexpectedly, GFAP expression fell rather than rose, leading the authors to propose that COPRP guides astrocytes away from a chronically hyperactivated, potentially neurotoxic phenotype toward a protective, repair-oriented state.

The causal test came from pirfenidone, an antifibrotic agent that attenuates TGF-β-associated signaling. Rats pretreated with pirfenidone before lesioning and COPRP treatment showed substantially reversed TGF-β2 expression and Smad2/3 phosphorylation, and their behavioral recovery across rotational, cylinder, and open-field tests was significantly blunted, though still better than untreated Parkinsonian rats. The authors acknowledge the limits of this design: systemic pirfenidone given before modeling cannot isolate striatal TGF-β signaling, so the data support the pathway as an important mediator without establishing pathway-specific causality. They also note that the study could not establish clinical or pharmacoeconomic advantages over established levodopa regimens, since the current approach requires stereotactic intracranial administration and specialized biomaterial preparation. Long-term biosafety, biodistribution of degradation products, and cell-type-specific knockout models to pinpoint the cellular targets of COPRP-mediated neuroprotection remain future work. Still, the framework is clear: a structurally defined fructan from a traditional medicinal herb, chemically functionalized into an injectable self-healing matrix, can couple local drug release with active immunomodulation and neuroprotection, positioning polysaccharide hydrogels as bioactive therapeutic agents rather than passive depots in the fight against neurodegeneration.

Subject of Research: A bioactive oxidized Polygonati rhizoma polysaccharide crosslinked chitosan hydrogel that modulates TGF-β/Smad signaling for Parkinson's disease treatment

Article Title: 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

Article References: Dai, P., Zhao, J., Xue, C., Xu, K., Yong, L., Zhang, Z., Huang, Y., Shuai, J., Chen, X., Nie, S., & Xu, J. (2026). 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. Advanced Science, Article e77842. https://doi.org/10.1002/advs.77842

Image Credits: AI Generated

DOI: 10.1002/advs.77842

Keywords: Parkinson's disease, hydrogel, Polygonatum sibiricum, polysaccharide, TGF-β/Smad signaling, levodopa, neuroinflammation, oxidative stress, Schiff base reaction, dopaminergic neurons, proteomics, drug delivery