Intrinsically Strain-Stiffening, Conductive, ROS-Scavenging Peptide–Polymer Hydrogel to Promote Neurite Outgrowth

Abstract

Neurodegenerative disorders pose a major global health challenge due to impaired electrical signaling in nerve fibers, yet effective regenerative therapies remain limited. Here, we report an injectable hydrogel that integrates intrinsic conductivity, antioxidative capacity, and strain-stiffening mechanics, to emulate key features of the neural extracellular matrix (ECM) and promote neuronal differentiation. We design peptide amphiphiles (Fcn, n = 5, 10) by anchoring a redox-active ferrocene (Fc) motif to a self-assembling peptide segment (NVFFAKKC) via methylene spacers (n). These nanofibers are dynamically cross-linked with a thermoresponsive polymer, PDMA, via Schiff-base chemistry to furnish Fcn-PDMA hydrogels exhibiting tunable electrical conductivity, potent radical-scavenging ability, and nonlinear strain-stiffening behavior. Notably, the hydrogels display both heat- and strain-induced stiffening behavior reminiscent of fibrin networks. In vitro experiments show that SH-SY5Y neuroblastoma cells encapsulated in these hydrogels, particularly Fc10-PDMA, exhibit excellent biocompatibility, resistance to oxidative stress, and enhanced neurite outgrowth. Taken together, the multifunctional hydrogels provide a biomimetic 3D niche that leverages electrical, mechanical, and redox cues to synergistically promote neurogenesis.