Supramolecular strategy for compartment pathogen clearance and immuno-metabolic homeostasis to treat periodontitis

Abstract Periodontitis is an inflammatory disease driven by bacterial infection and immune dysfunction. Immune-subversive bacteria in the periodontitis microenvironment, such as Porphyromonas gingivalis , can evade conventional therapies by invading cells and inducing lysosomal dysfunction. Here we develop an injectable supramolecular hydrogel through the co-assembly of recombinant human type I collagen (COL), poly-ε-lysine (PL), and puerarin (PUE). Supramolecular amorphization improves PUE’s solubility and permeability, enabling a dual-compartment antibacterial strategy via effective trans-barrier delivery. Extracellularly, PL and PUE synergistically disrupt bacterial membranes and metabolism, while concurrently mitigating bacterial toxin induced pro-inflammatory macrophage polarization. Intracellularly, the supramolecular complexes facilitate PUE accumulation in phagolysosomes. By counteracting local oxidative stress, the internalized PUE restores lysosomal acidification and alleviates bacteria-induced immuno-metabolic dysregulation. In vivo, the hydrogel manipulates the local inflammatory microenvironment and facilitates periodontal tissue repair. This study provides a clinically translatable supramolecular strategy for treating intracellular infections and restoring tissue homeostasis.