Injectable cationic dynamic hydrogel with supramolecular drug loading reprograms neutrophil fate to alleviate diabetic periodontitis

The pervasive infiltration of tissue-destructive yet microbicidal-impaired neutrophil extracellular traps (NETs) constitutes a primary mechanistic driver of diabetic periodontitis refractoriness. Apoptosis facilitates nonphlogistic turnover of neutrophils, but excessive activation leads to the release of an excessive amount of dysfunctional NETs, causing tissue damage in diabetic periodontitis. To co-target pathological NETosis and dysbiotic infection, we engineered an injectable cationic dynamic hydrogel (ICDH) with supramolecular drug loading via grafting phenylboronic acid onto cationic poly-L-lysine, crosslinking with polyvinyl alcohol via dynamic borate esters, and loading immunomodulatory agents (chlorogenic acid and metformin) via supramolecular interactions. This innovative design confers robust tissue adhesion, microenvironmental responsivity to pH/glucose/ROS, enabling broad-spectrum antibacterial efficacy against <i>S. aureus</i>, <i>E. coli</i>, and keystone pathogen <i>P. gingivalis</i>, exceptional biocompatibility, alongside significant attenuation of periodontal inflammation and alveolar bone loss. Host transcriptomics revealed ICDH reprograms neutrophil fate from NETosis to apoptosis and suppresses osteoclastogenesis, while dual RNA-seq of neutrophil-<i>P. gingivalis</i> cocultures suggested concurrent modulation of porphyrin metabolism across host-microbial compartments, thereby restoring interfacial homeostasis. Collectively, ICDH establishes a novel therapeutic modality for refractory diabetic periodontitis via simultaneous immune-microbial crosstalk regulation, offering a translational and clinically deployable strategy.