Nanomaterial-based STING inhibition for accelerating bone defect repair via photothermal-responsive hydrogel delivery

Bone defects caused by trauma, infection, tumors, or osteoporosis pose significant clinical challenges, especially with rising fracture incidence in aging populations. The regulation of immune microenvironment in bone defect lesions by drug-loaded hydrogel has been shown to accelerate bone healing. In this study, we developed a photothermal-responsive hydrogel (GMHD/TFe@Aca) loaded with acacetin, a natural flavonoid with anti-inflammatory and immunomodulatory properties. The hydrogel loaded with TFe@Aca nanoparticles exhibited excellent mechanical properties, biocompatibility, and low cytotoxicity. In a mouse model of bone defect, this photothermal-responsive hydrogel facilitated sustained drug release at the bone defect site, with the drug release rate controlled through light stimulation. Acacetin was found to inhibit stimulator of interferon genes (STING) activation, suppress M1 macrophage polarization, and promote M2 polarization. Near-infrared (NIR)-triggered acacetin release further accelerated bone repair by reducing inflammatory cytokines, promoting collagen synthesis, and enhancing angiogenesis. These findings highlight GMHD/TFe@Aca as a multifunctional material capable of modulating inflammation and promoting bone regeneration, offering a promising strategy for bone defect treatment and advancing biomaterial development in regenerative medicine.