Reinstating Niche Failure in Diabetic Cranial Defects via Chronotaxic Signal-Amplifying Fluidic Biomimetic Hydrogel

Cranial stem cell niches (SCNs) are intrinsically scarce and hypoactive, and, exacerbated by chronic inflammation in diabetes, lead to niche failure and regenerative deficit after injury. Herein, an in situ moldable fluidic biomimetic niche (GelSSO/PDA@SDF) is developed as a chronotaxic signal amplifier to enhance SCN abundance and activity, aiming to restore autonomous regeneration. This biomimetic niche integrates PDA@SDF nanoparticles and a GelSSO hydrogel precursor, synthesized via dopamine self-polymerization/protein coupling and sequential methacrylation/sequence-specific oligodeoxynucleotide (SSO) grafting, respectively. Photocrosslinked GelSSO/PDA@SDF can preferentially and sustainably release PDA@SDF nanoparticles to trigger early-phase signal amplification, characterized by SDF-1α/CXCR4-mediated recruitment of endothelial and mesenchymal progenitors, vascular niche activation driving AKT-dependent angiogenesis, and suppressed M1 macrophage dominance. Progressive hydrogel degradation initiates the secondary signal amplification phase, in which prolonged SSO release creates a transcriptionally active osteogenic niche for MAPK/ERK-induced osteogenesis. In vivo, the in situ structured GelSSO/PDA@SDF conformed to defect geometry, promoting the early establishment of an immunologically favorable, progenitor-enriched niche through local immunomodulation and endogenous cell homing, followed by successive activation of vascular and osteogenic niches, ultimately achieving diabetic cranial vascularized bone regeneration. Thus, this chronotaxic signal-amplifying biomimetic niche offers a versatile strategy for restoring autonomous regeneration in the diabetic cranium and other poorly regenerative tissues.