Ph/Ros-Responsive Microneedle Patch For Immunomodulation In Periodontitis

Aim or purpose: Periodontitis involves immune dysregulation driving neutrophil extracellular traps (NETs) and osteoclast activation, damaging periodontal tissue. Herein, we investigated a treatment using the hydrogel microneedle patch with multilevel structures, including a pH/ROS-responsive base for drug controlled-release, a degradable tip for drug sustained-release and an antibacterial substrate. Dehydroepiandrosterone (DHEA) and mangiferin are loaded into microneedles to stimulate endothelial cell-derived developmental endothelial locus-1 (DEL-1) release, thereby suppressing neutrophil recruitment, inhibiting NETs formation and reversing osteoblast-osteoclast imbalance, ultimately reducing periodontal tissue damage. Materials and methods: In vitro experiments were conducted using bone marrow mesenchymal stem cell (BMSCs), human umbilical vein endothelial cells (HUVECs) and neutrophils isolated from mouse. NETs formation was visualized via confocal microscopy. Quantitative real-time polymerase chain reaction, western blot assay and transcriptome sequencing were used for the assessment of associated gene expression. In vivo immunomodulation properties were validated through rat model with periodontitis (Ethic committee. 2025000725). Micro-CT and immunohistochemical staining were utilized for the measurement of the periodontitis damage. Results: The dual-layer microneedle patch exhibited adequate mechanical strength, pH/ROS-responsive properties, and excellent biocompatibility, fulfilling clinical application requirements. Under DHEA/mangiferin stimulation, HUVECs significantly upregulated DEL-1 secretion, which markedly suppressed neutrophils adhesion, NETs formation and enhanced inflammatory osteogenic regeneration. In vivo results demonstrated that drug-loaded microneedle patch effectively reduced periodontal tissue destruction and enhanced alveolar bone repair. Conclusions: The DHEA/mangiferin-loaded microneedle patch demonstrated superior periodontal immunomodulatory efficacy and tissue-protective functions, offering a novel therapeutic strategy for clinical periodontitis management.