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

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.