Inflammation-responsive biodegradable nanocomposite hydrogels for enhanced metalloimmunotherapy in chronic...

Metalloimmunotherapies are emerging as promising treatment for cancer and infectious diseases by harnessing immune responses involving metal ions. However, their potential role in tissue regeneration remains unclear. In the context of chronic periodontitis, an inflammatory disease characterized by accumulated inflammatory cells and progressive alveolar bone loss, we report new effects of copper on inflammatory resolution and alveolar bone regeneration by enhancing lymphatic drainage. We first construct an injectable and thermosensitive hydrogel using catechol-conjugated chitosan (CHI-C) and pluronic F-127 (PF-127) to enhance the adhesive capacity of nanocomposite. Then, copper-containing mesoporous bioactive glass nanoparticles (Cu-BGs) are fabricated for sustained release of copper ions in acidic environments and mixed with VEGFC (a growth factor increasing lymphangiogenesis) into the hydrogel (Cu/VEGFC@Hy). We confirm the in vitro impact of copper on proliferation and migration of lymphatic endothelial cells (LECs) and smooth muscle cells (SMCs), key components of collecting lymphatic vessels. RNA-seq analysis reveals that copper promotes proliferation in LECs and SMCs by targeting COX4i2/ERK pathway. In periodontitis model, Cu/VEGFC@Hy significantly improves the reconstruction of collecting lymphatic vessels, accelerating lymphatic drainage and rejuvenating alveolar bone mass. Overall, the well-designed Cu/VEGFC@Hy effectively reduces inflammatory accumulation by promoting lymphatic vessel formation and tissue regeneration in inflammatory diseases. STATEMENT OF SIGNIFICANCE: This study introduces a pioneering metalloimmunotherapy approach for chronic periodontitis, utilizing copper ions to enhance lymphatic drainage and alveolar bone regeneration. We developed an injectable, thermosensitive hydrogel incorporating copper-containing mesoporous bioactive glass nanoparticles and VEGFC, which synergistically promotes the reconstruction of collecting lymphatic vessels and reduces inflammatory accumulation. Our findings reveal a novel mechanism where copper ions stimulate the proliferation and migration of lymphatic endothelial and smooth muscle cells via the COX4i2/ERK pathway. This work not only offers a promising biomaterial-based therapy for periodontitis but also broadens the application of metal ions in tissue engineering and regenerative medicine, with potential implications for other inflammatory diseases.