Co-Releasing Nanoparticles Accelerate Mandibular Vascularized Bone Regeneration

This study innovatively constructs red light-responsive carbon monoxide (CO)-releasing nanoparticles (COR-NPs) to accelerate vascularized mandibular regeneration through a triple synergistic mechanism: red light-triggered ROS scavenging, localized oxygen depletion, and controlled CO release, thereby reconstructing the defective microenvironment. COR-NPs were synthesized via a self-assembly method, followed by characterization of CO release efficiency and dissolved oxygen levels. Experimental groups included control group, red-light group, blank-NPs group, and COR-NPs group. In vitro cellular experiments were performed to evaluate the anti-inflammatory, pro-angiogenic, and osteogenic effects of COR-NPs using immunofluorescence staining, osteogenic induction, and tube formation assays. Antibacterial efficacy against Staphylococcus aureus and Streptococcus mutans was assessed via turbidimetry, live/dead staining, and crystal violet assays. A tooth extraction model in 8-week-old male Sprague-Dawley rats (approved by the Ethics Committee) was employed to analyze jawbone regeneration through micro-CT and immunohistochemical staining. Compared to controls, COR-NPs effectively consumed intracellular ROS to suppress neutrophil extracellular trap formation. Meanwhile, COR-NPs established a transient hypoxic microenvironment, activating the HIF pathway to enhance microvascular reconstruction and mitochondrial metabolic reprogramming. Concurrently, CO release inhibited bacterial proliferation, amplified neutrophil phagocytic efficiency, and bolstered the stress resistance and osteogenic differentiation of bone marrow mesenchymal stem cells. This work elucidates the dynamic regulatory principles of mandibular regeneration from a gas molecule-microenvironment interaction perspective. The COR-NPs demonstrate significant potential in accelerating vascularized bone regeneration through remodeling microenvironments, offering a novel strategy for craniofacial tissue engineering.