Macrophage-Targeted Self-Assembled Nanosystem for Periodontitis Treatment.

Periodontitis is a chronic inflammatory disease triggered by pathogenic bacteria, with intracellular bacteria and biofilm contributing to persistent periodontal inflammation. In this context, macrophages can be portrayed as a privileged niche for long-term bacterial colonization, leading to further disruption of the immune microenvironment rather than its modulation. Here, a macrophage-targeted metal-organic/polyphenol self-assembly nano drug delivery system was designed for on-site drug delivery and microenvironment restoration. The nanoparticles were synthesized by hyaluronic acid functionalization on the surface of curcumin (Cur)-loaded zeolitic imidazolate framework-8 (denoted as ZCH NPs). ZCH NPs selectively targeted macrophages through CD44 receptor-mediated endocytosis. Following cellular uptake, the nanoparticles underwent pH-responsive degradation in the acidic lysosomal environment (~pH5), releasing zinc ions and Cur. The dual release exerted optimal therapeutic effects, including anti-inflammatory and immunomodulatory activities, through the PPAR/Notch signaling pathways. Furthermore, ZCH NPs restored the osteogenic potential of stem cells in an inflammatory environment by rebalancing the immune microenvironment. ZCH NPs also eliminated extracellular and intracellular bacteria and inhibited biofilm formation. Ultimately, ZCH NPs alleviated inflammatory bone resorption in rat experimental periodontitis, with the reduction of cementoenamel junction-alveolar bone crest from ~568 to ~250 µm. Therefore, periodontal tissue regeneration was promoted by eradicating pathogenic bacteria, modulating immune response, and facilitating osteogenic differentiation. Collectively, through on-site and responsive drug delivery, ZCH NPs exhibited superior efficacy in treating periodontitis, providing a promising strategy for addressing infection-related chronic inflammatory diseases.