Bioinspired nano-micron hydrogel microspheres for periodontitis therapy through synergistic multi-targeted remodeling of microenvironment

Background: Periodontitis is a prevalent oral inflammatory disease that leads to alveolar bone resorption and tooth loss. It is hard to control and prone to recurrence. Current treatments often fall short due to deep, tortuous periodontal pockets and antibiotic-resistant bacteria, such as Fusobacterium nucleatum (F. nucleatum). Notably, current clinical therapies fail to simultaneously fulfill three critical objectives: robust antimicrobial efficacy, potent anti-inflammatory activity, and effective periodontal regenerative capacity. Methods: Inspired by the structure of the lotus flower, nano/micron-combined hydrogel microspheres (PDA/BBR@Gel@BMP9-PDLSC), encapsulating polydopamine (PDA) nanoparticles carrying berberine (PDA/BBR) and BMP9-infected PDLSCs (BMP9-PDLSC), were developed. Results: Microspheres exhibited excellent biocompatibility and sustained drug release, along with significant antibacterial, anti-inflammatory, and bone tissue regenerative effects. In vivo studies confirmed their efficacy in treating calvaria defects and periodontitis with persistent F. nucleatum infection, showing superior new bone formation and anti-inflammatory effects without organ toxicity. Notably, our study demonstrated that the anti-inflammation and osteogenesis effects were due to the synergistic effects of BBR and BMP9 released by PDA/BBR@Gel@BMP9-PDLSC microspheres. RNA-Seq and Western blot analysis showed that BBR and BMP9 synergistically reduced inflammation and promoted bone formation by regulating key genes involved in TNF, TGF-β, and PPAR signaling pathways. Conclusions: Our study provides a novel approach for comprehensively treating periodontitis with antibacterial, anti-inflammatory, and bone tissue regenerative effects.