Gradient regulation of osteo-immune microenvironment by chitooligosaccharide-containing ion-doped mesoporous silica nanoparticles to accelerate osteogenesis

•Well degradation performance of MSNion was attributed to the multiple ions (Zn, Ca, Sr) doping. COS was loaded into MSNion (MSNion-COS) successfully.•The inflammatory cell was activated by MSNion-COS in early stage, showing the pro-inflammatory property.•The anti-inflammatory property of the MSNion-COS was clearly observed in the latter stage, which further activated the osteogenic differentiation.•MSNion-COS fully demonstrated the gradient regulation of osteo-immune environment, benefiting for accelerating osteogenesis. Tissue repair can be induced subsequently by the early inflammatory response after biomaterial implantation. However, the accomplishment of late regeneration process requires inhibit inflammation. This study aims to realize the gradient regulation of osteogenic immune micro-environment regenerating lost bone tissues by utilizing the synergistic effect of chitooligosaccharides (COS) and inorganic ions. Zinc (Zn)-Calcium (Ca)-Strontium (Sr) doped mesoporous silica nanoparticles (MSN) (denoted as MSNion) was successfully produced by cetyltrimethylammonium-bromide-mediated template method and its phase, morphology, structure, physicochemical properties, in vitro degradability were studied here. Results indicated that Si4+, Zn2+, Ca2+ and Sr2+ were incorporated into MSN and significant improvement can be viewed on the degradation performance of MSNion. COS was successfully loaded into MSNion (MSNion-COS), and the ability to gradient regulation of osteo-immune environment was investigated. Noticeably, the inflammatory cell was activated by MSNion-COS in early stage because of ions release, showing the pro-inflammatory property. In the latter stage, we can clearly observe the anti-inflammatory property of the MSNion-COS with upregulating the anti-inflammatory cytokines secretion, which further activated the osteogenic differentiation. Specifically, osteogenesis-related genes (Alkaline phosphatase (ALP), Osteocalcin (OCN), Osterix (OSX), and runt-related transcription factor 2 (RUNX2)) and the degree of calcium deposition of bone marrow mesenchymal stem cells (BMSCs) were significantly upregulated in the later anti-inflammation environment of macrophages modulated by MSNion-COS. Results suggested that MSNion-COS fully demonstrated the gradient regulation of osteo-immune environment, benefiting for accelerating osteogenesis. [Display omitted]