Intracellular tension relaxation engineered through D-enantiomeric hydrogel maneuvers neurogenesis and immunomodulation to facilitate spinal cord repair

Microenvironment mechanics plays a vital role in regulating morphogenesis and immune response after injury, but their exploration has been hindered by the fragile mechanical strength and oxidative physiological environment in spinal cord injury (SCI). Here, we engineered self-assembly hydrogels of enantiomeric peptides with neural tissue-matching mechanical properties to persistently manipulate cellular membrane tension and mechanotransduction through stereo conformational recognition and consequent protein affinity difference. The D-enantiomeric hydrogel-induced intracellular tension relaxation activates neurogenesis and ECM remolding in astrocytes, suppresses pro-inflammation and promotes pro- regeneration in microglia, which significantly facilitates neuroprotection and functional recovery in a rat severe SCI model. The intracellular tension relaxation-induced morphogenesis may be neural characteristics, contrary to non-neural cells, as the downstream mechanical signaling is activated by the resulted neurogenic morphology change. Overall, inducing intracellular tension relaxation is a potential effective strategy for promoting nerve regeneration.