Dual-Functional Nanotherapy-Reinforced Hydrogel for Synergistic Antimicrobial and Immunomodulatory Oral Tissue Repair

Conventional hydrogels exhibit inadequate performance in oral applications due to poor bioadhesion and uncontrolled drug release in saliva-rich dynamic environments, compromising their antimicrobial and anti-inflammatory effects. To address these limitations, we propose a nanotherapy-reinforced multifunctional hydrogel strategy. Curcumin (CUR)/polyaminopropyl biguanide (PAPB) nanoparticles (CP NPs) are first prepared by electrostatic interaction-mediated self-assembly of the anti-inflammatory/antioxidant drug CUR and the antibacterial polymer PAPB. This multibioactive nanotherapy shows ultrahigh loading contents for both therapeutic agents (47% CUR, 42% PAPB). Further integrating CP NPs into a photo-cross-linkable hydrogel based on gelatin methacryloyl and oxidized hyaluronic acid affords functionally multifaceted networks reinforced by hydrogen bonding, electrostatic force, and Schiff base, enabling dynamical modulation of hydrogel properties. The resultant hybrid hydrogel exhibits programmable mechanical adaptability, including tunable viscoelasticity, shear-thinning behavior, and controllable swelling/degradation, along with robust tissue adhesion (∼80 kPa) for <i>in situ</i> barrier formation on irregular defects. Additionally, it provides sustained codelivery of CUR/PAPB (>72 h) with synergistic antibiofilm and immunomodulatory functions. <i>In vivo</i> evaluations across skin wound, oral ulcer, and periodontitis models demonstrate prolonged microbial defense, significant inflammation resolution, and accelerated tissue regeneration. This nanotherapy-mediated multi-interaction reinforcement strategy can serve as a versatile approach for engineering self-adaptive hydrogels to address complex challenges in oral regenerative medicine.