Cascade-Targeting Nanoparticles In Ros-Responsive Hydrogel Treating Diabetic Periodontitis

To address the more severe and uncontrollable inflammation caused by elevated blood sugar in diabetic periodontitis, we have developed a novel cascade-targeting nanoparticle (MPPT) encapsulated in ROS-responsive hydrogel (MPPT@TSPBA-PVA), which enables responsive release of MPPT in oxidative stress microenvironment to target pro-inflammatory macrophages and deliver the mitochondria-targeting drug to restore mitochondrial redox balance. After confirming successful synthesis of MPPT and TSPBA-PVA, fluorescence imaging and flow cytometry validated the M1-targeting ability of MPPT. ROS levels and mitochondria biofunction were monitored by fluorescence dyes using SIM. RT-qPCR and Western Blot further elucidated MPPT’s anti-inflammatory pathway per RNA transcriptome analysis. Osteogenic ability of rBMSCs was evaluated with ALP, ARS and RT-qPCR. In vivo, clinical evaluation, micro-CT, H&E staining, immunohistochemistry and immunofluorescence evaluated the anti-inflammatory efficacy and mechanism in rat diabetic periodontitis model. Statistical analysis of the data was conducted on GraphPad Prism 10.0, and p<0.05 was considered statistically significant. ROS-responsive hydrogel degraded responsively in the presence of hydrogen peroxide, steadily releasing encapsulated MPPT. MPPT targeted pro-inflammatory M1 macrophages through folate receptor, while mitochondria-targeted drugs reduced abnormal mitochondrial ROS production and improved mitochondria functions. Both in vitro and in vivo studies demonstrated effective alleviation of oxidative stress and inflammation, with NLRP3 pathway downregulation. We synthesize cascade-targeting MPPT nanoparticles in ROS-responsive TSPBA-PVA hydrogel to release MPPT accordingly and effectively alleviate diabetic periodontitis by improving mitochondrial function and downregulating NLRP3 pathway.