International journal of nanomedicine · 2026
Anion-Dependent Layered Double Hydroxide-Reinforced Gelatin Methacryloyl Hydrogels for Osteoimmunomodulation and Bone Regeneration.
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Wang Zhong, Shi Mengle, Xu Hao, Huang Huanbin, Xing Jin, Gu Qinwei, Wang Siyu, Zheng Jiajie
Аннотация
PURPOSE: Persistent inflammation and insufficient osteogenesis jointly limit the repair of critical-sized bone defects. This study aimed to develop an anion-programmable osteoimmunomodulatory hydrogel based on magnesium-aluminum layered double hydroxide (LDH) nanoparticles and gelatin methacryloyl (GelMA), determine whether LDH interlayer anions regulate immune-skeletal crosstalk, and evaluate whether this strategy enhances repair of critical-sized calvarial bone defects.
METHODS: Chloride- and nitrate-intercalated MgAl-LDH nanoparticles (LDH-Cl- and LDH-NO3 -) were synthesized and characterized. Their cytocompatibility, cellular uptake, macrophage-polarizing effects, and osteogenic activity toward bone marrow mesenchymal stem cells (BMSCs) were evaluated in vitro. LDH nanoparticles were incorporated into photocrosslinked GelMA hydrogels and assessed in a murine critical-sized calvarial defect model. Transcriptomic sequencing was performed with three biological replicates per group, and cell-type-specific qRT-PCR was used to validate representative pathway-associated genes in vitro.
RESULTS: Thoroughly washed low- and high-magnification confocal images demonstrated FITC-LDH association/internalization in macrophages and BMSCs without apparent cytotoxicity. In lipopolysaccharide-activated macrophages, LDH nanoparticles reduced TNF-α and IL-1β expression while increasing TGF-β and IL-10 expression, with LDH-NO3 - producing the strongest macrophage repolarization. LDH-NO3 - also enhanced alkaline phosphatase activity, extracellular matrix mineralization, and osteogenic gene expression in BMSCs. After incorporation into GelMA hydrogels, LDH-NO3 - promoted greater defect bridging, bone mineral density, collagen deposition, and osteocalcin expression in vivo. Transcriptomic analysis was consistent with increased PI3K/Akt-associated regenerative signaling and attenuation of NF-κB-associated inflammatory programs, and in vitro qRT-PCR showed concordant Akt1 and Rela transcriptional changes.
CONCLUSION: Interlayer anion engineering of LDH nanoparticles, particularly nitrate intercalation, provides a strategy for constructing immunoactive GelMA-based hydrogels that coordinate inflammation resolution and osteogenic repair in critical-sized bone defects.
METHODS: Chloride- and nitrate-intercalated MgAl-LDH nanoparticles (LDH-Cl- and LDH-NO3 -) were synthesized and characterized. Their cytocompatibility, cellular uptake, macrophage-polarizing effects, and osteogenic activity toward bone marrow mesenchymal stem cells (BMSCs) were evaluated in vitro. LDH nanoparticles were incorporated into photocrosslinked GelMA hydrogels and assessed in a murine critical-sized calvarial defect model. Transcriptomic sequencing was performed with three biological replicates per group, and cell-type-specific qRT-PCR was used to validate representative pathway-associated genes in vitro.
RESULTS: Thoroughly washed low- and high-magnification confocal images demonstrated FITC-LDH association/internalization in macrophages and BMSCs without apparent cytotoxicity. In lipopolysaccharide-activated macrophages, LDH nanoparticles reduced TNF-α and IL-1β expression while increasing TGF-β and IL-10 expression, with LDH-NO3 - producing the strongest macrophage repolarization. LDH-NO3 - also enhanced alkaline phosphatase activity, extracellular matrix mineralization, and osteogenic gene expression in BMSCs. After incorporation into GelMA hydrogels, LDH-NO3 - promoted greater defect bridging, bone mineral density, collagen deposition, and osteocalcin expression in vivo. Transcriptomic analysis was consistent with increased PI3K/Akt-associated regenerative signaling and attenuation of NF-κB-associated inflammatory programs, and in vitro qRT-PCR showed concordant Akt1 and Rela transcriptional changes.
CONCLUSION: Interlayer anion engineering of LDH nanoparticles, particularly nitrate intercalation, provides a strategy for constructing immunoactive GelMA-based hydrogels that coordinate inflammation resolution and osteogenic repair in critical-sized bone defects.