Enantiomeric Hydrogel-Manipulated Mechanotransduction Triggers Neurogenesis and Immunomodulation for Spinal Cord Repair

Microenvironmental mechanics regulate morphogenesis and post-injury inflammation, however, the fragile mechanical strength and oxidative physiological environment hinder precise and consistent mechanical management after spinal cord injury (SCI). Here, we engineered self-assembling hydrogels of enantiomeric peptides with neural tissue- matching mechanical properties to persistently manipulate mechanosensing and mechanotransduction through stereo conformational recognition and consequent protein affinity difference. While hindering proliferation and morphogenesis in non-neural cells, D-hydrogel-induced intracellular tension relaxation triggered neurogenesis and ECM remolding in astrocytes, while simultaneously suppressing pro-inflammation and promoting pro-regeneration in microglia, which together enable neuroprotection from degeneration and enhance functional recovery in severe SCI rat models. These effects are mediated through neurogenic morphology changes resulting from cytoskeletal tension relaxation, leading to the opening of mechanosensitive ion channels in the cellular membrane, chromatin unfolding, and YAP nuclear translocation. This exclusive D- hydrogel-dependent neurogenesis, triggered by intracellular tension relaxation, revealed a neural-specific response to mechanical cues and provided a targeted tissue repair strategy for nerve injury.