Enhancing bone healing through immunological microenvironment modulation via a smart-responsive multifunctional therapeutic system

The clinical repair of bone defects is still a significant challenge because of unfavorable immunological microenvironments, limited blood supply, and weak osteogenic differentiation potential. Therefore, a hydroxyapatitebased (HAp) nanocomposite (HPDD), consisting of polydopamine (PDA)-adhered deferoxamine (DFO), was designed and incorporated into an F127DA hydrogel. The HPDD nanocomposite acted as a photosensitizer, endowing the F127DA/HPDD hydrogel with the ability to spatiotemporally and intelligently release DFO and Ca2+ in response to near-infrared (NIR)/pH stimulation. This mild photothermal therapy induced by NIR irradiation achieves the clearance of reactive oxygen species (ROS), the polarization of M1 macrophages toward the M2 phenotype, and the promotion of angiogenesis and bone repair. Furthermore, by fostering an antiinflammatory immunological microenvironment, the F127DA/HPDD hydrogel sustained release system promoted the secretion of functional factors, which are beneficial for angiogenesis and bone repair. Transcriptomic analysis was employed to investigate how M2 macrophage polarization enhances angiogenesis and osteogenic differentiation. In vivo experiments further confirmed that the F127DA/HPDD hydrogel system, under NIR/pH stimulation, promoted angiogenesis and osteogenic differentiation by inhibiting inflammation. In summary, this intelligent responsive hydrogel system provides a novel approach for reshaping an anti-inflammatory immunological microenvironment to accelerate bone repair.