Trehalose‐Guanosine Glycopolymer Hydrogels Direct Adaptive Glia Responses in CNS Injury

Neural tissue damaged after central nervous system (CNS) injury does not naturally regenerate but is instead replaced by non‐neural fibrotic scar tissue that serves no neurological function. Scar‐free repair to create a more permissive environment for regeneration requires altering the natural injury responses of glial cells. In this work, glycopolymer‐based supramolecular hydrogels are synthesized to direct adaptive glia repair after CNS injury. Combining poly(trehalose‐co‐guanosine) (pTreGuo) glycopolymers with free guanosine (fGuo) generates shear‐thinning hydrogels through stabilized formation of long‐range G‐quadruplex secondary structures. Hydrogels with smooth or granular microstructures and mechanical properties spanning three orders of magnitude are produced through facile control of pTreGuo hydrogel composition. Injection of pTreGuo hydrogels into healthy mouse brains elicits minimal stromal cell infiltration and peripherally derived inflammation that is comparable to a bioinert methyl cellulose benchmarking material. pTreGuo hydrogels alter astrocyte borders and recruit microglia to infiltrate and resorb the hydrogel bulk over 7 d. Injections of pTreGuo hydrogels into ischemic stroke alter the natural responses of glial cells after injury to reduce the size of lesions and increase axon regrowth into lesion core environments. These results support the use of pTreGuo hydrogels as part of neural regeneration strategies to activate endogenous glia repair mechanisms. Glycopolymer‐based supramolecular hydrogels are formulated by combining poly(trehalose‐co‐guanosine) (pTreGuo) glycopolymers with free guanosine (fGuo). Hydrogels with tunable microstructures and mechanical properties are produced through facile control of pTreGuo composition and fGuo concentration which alters G‐quadruplex assembly. pTreGuo hydrogels direct adaptive glia repair responses after ischemic stroke to reduce the size of lesions and increase axon regrowth into lesion core environments.