Histatin1-Functionalized Hydrogel For Multidimensional Sequential Modulation In Periodontitis

Designing a histatin1-based anti-inflammatory osteogenic dual-effect gene delivery hydrogel for sequential immuno-osteogenic modulation, targeting fibrin deposition and promoting alveolar bone regeneration in periodontitis. We created a histatin1-based hydrogel for dual anti-inflammatory and osteogenic effects, targeting fibrin deposition and bone regeneration in periodontitis. In vitro studies demonstrated its regulatory effects on neutrophils, BMSCs, and PDLSCs, mediating immunomodulatory osteogenesis. In vivo, 6-week-old male SD rats were randomly divided into four groups: blank control, positive control, histatin1-miRNA solution, and the hydrogel. Chronic periodontitis was induced by bilateral maxillary second molar ligation. Anti-inflammatory and bone regeneration effects were evaluated at 2 weeks, 1, 2, and 3 months post-application via CT and staining. Approved by related Animal Ethics Committee (No. 32300). 1. The histatin1-functionalized hydrogel was successfully synthesized, showing excellent mechanical and biological properties. Its porous structure enabled storage and sustained release of histatin1-miRNA, supporting long-term periodontitis treatment. 2. The histatin1-functionalized hydrogel demonstrated superior cellular uptake efficiency and mitochondrial targeting, with peak effects at 12 hours. 3. In the early stages, the hydrogel not only inhibited fibrin synthesis and enhanced anti-inflammatory effects but also modulated the osteoimmune microenvironment and induced in situ bone regeneration. Moreover, the hydrogel ensured prolonged release of histatin1-miR200c, promoting continuous periodontal tissue repair and achieving sequential regulation of the periodontal immuno-osteogenic microenvironment. We developed a novel anti-inflammatory and osteogenic dual-effect gene delivery system that enabled multidimensional periodontitis therapy.