Aqp9-Modulating Hydrogel Suppresses Osteoclast Activity In Periodontitis

Aim or purpose This study aimed to develop a multifunctional supramolecular hydrogel targeting aquaporin 9 (AQP9) to treat periodontitis by attenuating inflammation and inhibiting osteoclast differentiation. Materials and methods A peptide–drug amphiphile was synthesized by conjugating 3,5-dihydroxybenzoic acid (DHB), ibuprofen (IPF), and a self-assembling peptide motif (Gly-Phe-Phe-Tyr-Asp, GFFYD), yielding the compound 2IPF-DHB-GFFYD. This conjugate self-assembled into a matrix metalloproteinase-9 (MMP-9)-responsive supramolecular hydrogel. The hydrogel's physicochemical properties and drug release behavior were thoroughly characterized. In vitro and in vivo studies were conducted to evaluate its anti-inflammatory and bone-protective effects in a periodontitis model. Results A peptide–drug amphiphile was synthesized by conjugating 3,5-dihydroxybenzoic acid (DHB), ibuprofen (IPF), and a self-assembling peptide motif (Gly-Phe-Phe-Tyr-Asp, GFFYD), yielding the compound 2IPF-DHB-GFFYD. This conjugate self-assembled into a matrix metalloproteinase-9 (MMP-9)-responsive supramolecular hydrogel. The hydrogel's physicochemical properties and drug release behavior were thoroughly characterized. In vitro and in vivo studies were conducted to evaluate its anti-inflammatory and bone-protective effects in a periodontitis model. Conclusions This AQP9-targeting hydrogel offers a promising immunoregulatory strategy for the treatment of periodontitis. Its dual functionality—anti-inflammatory and anti-resorptive—provides new insight into biomaterial-based therapies and mitochondrial regulation in inflammatory bone diseases.