Versatile Microneedle Platform for Localized Immunomodulatory Therapy of Periodontitis Targeting the Reactive Oxygen Species/NF-κB Pathway

Periodontitis is a chronic disease characterized by periodontal tissue inflammation and alveolar bone resorption, in which regulating the immune microenvironment and controlling inflammation are primary therapeutic goals. However, current approaches are limited by the need for high systemic doses, insufficient local drug concentration, and short retention time. Herein, we developed a miRNA-126 nanoparticles@doxycycline dissolving microneedle patch (miR-126 NPs@DOX MN) for localized codelivery of miRNA-126 nanoparticles (miR-126 NPs) and doxycycline (DOX) to gingival tissue, aiming to achieve anti-inflammation and periodontal tissue regeneration. The MN possesses sufficient mechanical strength for gingival tissue penetration, resists salivary washout, and enables localized codelivery of miR-126 NPs and DOX, prolonging their retention within periodontal tissue. Moreover, the miR-126 NPs@DOX MN protects miRNA-126 from enzymatic degradation in the complex oral environment, preserving its bioactivity. Mechanistically, miRNA-126 and DOX, respectively, modulate the reactive oxygen species/NF-κB signaling pathway, thereby remodeling the immune microenvironment and alleviating inflammation. In vivo experiments further confirmed that the miR-126 NPs@DOX MN modulated macrophage polarization, not only reducing inflammation but also promoting alveolar bone regeneration. Collectively, the miR-126 NPs@DOX MN demonstrates potential as a localized therapeutic strategy for anti-inflammatory and immunomodulatory treatment of periodontitis.