Bioengineered α-Hairpin Peptide TKH with GKG Linker: A LLPS-Mediated Biomimetic Mineralization System for Intrafibrillar Remineralization and Deep Dentin Tubule Occlusion

Abstract Dentin hypersensitivity (DH) originates from collagen exposure and dentinal tubules (DTs) patency caused by mechanical abrasion or demineralization. For an effective long-term therapeutic desensitizing agent, the ability to achieve deep tubular occlusion, stable remineralization, and satisfactory biocompatibility simultaneously is essential. In this study, we designed a novel α-hairpin peptide, TKH, by incorporating a GKG linker into an α-helical template to enhance liquid–liquid phase separation (LLPS) and self-assembly for biomimetic mineralization. It effectively stabilizes calcium phosphate (CaP) and facilitates intrafibrillar mineralization within collagen fibrils. In vitro and in vivo remineralization studies combined with molecular dynamics (MD) simulations demonstrated that self-assembly sites provided by the GKG linker promotes the peptide self-assembly, hydroxyapatite (HA) adsorption, and amorphous calcium phosphate (ACP) infiltration, ultimately achieving intrafibrillar and extrafibrillar mineralization to seal DTs, alongside excellent biosafety. Accordingly, the peptide-based biomaterial TKH offers promising prospects for dentin remineralization and hypersensitivity management.