The immunomodulatory effects of DNA-conjugated collagen scaffolds on bone healing

• Deoxyribonucleic acid-crosslinked collagen (DNA-Col) scaffold exhibits improved osteogenesis when implanted into a bone defect. • Improved bone regeneration is attributed to the interaction of DNA-Col with T cells. • The DNA-Col scaffold promotes differentiation of T cells into Tregs via metabolic reprogramming. • The DNA-Col scaffold may be regarded as a bioactive bone regeneration material due to its immunomodulatory effects. Unmodified collagen scaffolds represent a bottleneck in bone tissue engineering. Because of their limited mechanical and osteoinductive properties, these scaffolds do not perform well in repairing large bone defects. To overcome these limitations, a deoxyribonucleic acid-crosslinked collagen scaffold (DNA-Col) is fabricated to enhance healing of bone defects. The DNA-Col induces rapid formation of new bone tissue in a rat alveolar bone defect model. However, the improved osteogenic performance is not directly attributed to DNA-Col, but to the interaction between DNA-Col and T cells. Mechanistic experiments further demonstrate that recruitment of regulatory T cells (Tregs) is significantly triggered by implantation of DNA-Col in vivo . This is supported by the reversal of DNA-Col-induced bone regeneration after depletion of Tregs. These results indicate that Tregs play an important role in DNA-Col-induced new bone formation. Further investigations reveal that DNA-Col promotes Treg differentiation via metabolic reprogramming. These exciting findings establish the role of DNA-Col as a bioactive bone regeneration scaffold via its capability to interact with Tregs. The present study paths the way for creating smart hard tissue engineering materials with modulatory functions on the osteo-immunologic environment of a surgical bone defect.