Injectable Hydrogel Loaded With Umbilical Cord Blood‐Derived Exosomes Promotes Periodontal Bone Regeneration via the TLR4/NF‐κB Signalling Pathway

ABSTRACT Periodontitis is an immune‐mediated inflammatory disease characterised by progressive alveolar bone loss, which can lead to tooth loss in severe cases. Existing therapeutic agents have limited efficacy in reversing the associated inflammatory bone defects. Exosomes (Exos), enriched with bioactive molecules, exhibit significant potential in anti‐inflammation and osteogenic regeneration. In this study, an injectable and photocurable composite hydrogel sustained‐release system (GA‐Exos) loaded with human umbilical cord blood‐derived exosomes (UCB‐Exos) was constructed. In vitro and in vivo experiments demonstrated that GA‐Exos possesses excellent performance, enabling sustained release of exosomes for approximately 21 days. It significantly promotes the proliferation and differentiation of osteoblasts, upregulates the expression of osteogenic markers (e.g., RUNX2, ALP, and OPN), reduces the levels of pro‐inflammatory cytokines (e.g., TNF‐α and IL‐1β), and inhibits inflammatory cell infiltration and osteoclast differentiation. mRNA sequencing and validation experiments confirmed that UCB‐Exos inhibits the activation of the TLR4/NF‐κB pathway by downregulating the expression of TLR4, LBP, and CD14, as well as the phosphorylation of P65. In conclusion, GA‐Exos enhances periodontal bone regeneration through the regulation of the TLR4/NF‐κB pathway, providing a novel and effective strategy for periodontitis treatment. This system is expected to break through the limitations of existing therapies and bring new insights for clinical applications.