Hierarchically Targeting and ROS-Responsive Platform for Diabetic Periodontitis Treatment through Mitochondrial Repair in M1 Macrophages

Diabetic periodontitis is characterized by persistent and aggravated inflammation, largely driven by a reactive oxygen species (ROS) vicious loop in M1 macrophages driven by mitochondrial dysfunction. To disrupt this pathogenic cascade, we developed hierarchically targeted polymeric nanoparticles (MPPT NPs) by conjugating the tuftsin peptide for selective uptake by M1 macrophages and loading mitoquinone mesylate (MitoQ) to restore mitochondrial function after mitochondrial localization. For local retention and responsive drug release, MPPT NPs were incorporated into a ROS-responsive hydrogel (MTP hydrogel) constructed by cross-linking poly(vinyl alcohol) (PVA) with a ROS-cleavable linker ( N 1 -(4-boronobenzyl)- N 3 -(4-boronophenyl)- N 1, N 1, N 3, N 3 -tetramethylpropane-1,3-diaminium (TSPBA)). This constructed platform not only enabled the on-demand release of MPPT NPs but also provided additional ROS-scavenging ability. In vitro studies demonstrated that MTTP NPs effectively repaired oxidatively damaged mitochondria and suppressed NLRP3 inflammasome priming and activation. MTP hydrogel platform reduced pro-inflammatory cytokine release and rescued inflammation-induced osteogenic impairment. In a diabetic periodontitis rat model, local administration of the MTP hydrogel significantly attenuated periodontal tissue destruction and promoted alveolar bone regeneration, achieving BV/TV 1.5 times that of previous reports. Collectively, this hierarchically targeted and ROS-responsive platform disrupts the ROS vicious loop in M1 macrophages by repairing damaged mitochondria, offering a promising therapeutic strategy for the management of diabetic periodontitis.