An antioxidative injectable chitosan hydrogel based on tannic acid modified dialdehyde polyurethane nano-crosslinker targeting RIPK1 to regulate neuroinflammation for amelioration of Parkinson's disease.

Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Currently, the treatment of PD is mainly based on surgery and medication, and there is a pressing necessity to develop a new generation of strategies incorporating biomaterials for treating PD. Herein, an antioxidative injectable chitosan hydrogel crosslinked with tannic acid-modified dialdehyde polyurethane nanoparticles (TA@DAP) to target RIPK1 is produced for ameliorating PD. The TA@DAP nano-crosslinker is newly synthesized via hydrogen bonding together with electrostatic interactions and is characterized by small angle X-ray with its data modeling, showing enhancement in dispersion stability, homogeneity, and bioactive capacity. The injectable hydrogel (CTDP) with sufficient modulus (∼180 Pa) exhibits rapid self-healing (∼7 min), shear-thinning injectability (30 gauge), and a uniform porous structure. In vitro, CTDP hydrogel significantly scavenges reactive oxygen species, promotes neural stem cell proliferation, and polarizes macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotypes. The CTDP hydrogel is injected into the brains of 6-hydroxydopamine-induced PD rats, demonstrating motor function restoration, dopaminergic neuron loss reduction, and suppression of neuroinflammation. Network pharmacology and molecular docking are employed to assist in screening for RIPK1-NF-κB-IκBα pathway as a key therapeutic mechanism. The bioactive injectable CTDP hydrogel provides a simple nanoparticle modification strategy integrated with advanced nanoscale characterization protocols while offering the possibility to explore the therapeutic mechanisms of composite biomaterials with network pharmacology and molecular docking, giving new concepts for the assessment of biomaterial preparations as well as for the treatment of PD.