Pathogenesis‐Guided Engineering of Multi‐Bioactive Hydrogel Co‐Delivering Inflammation‐Resolving Nanotherapy and Pro‐Osteogenic Protein for Bone Regeneration

Abstract There are still great challenges in promoting bone defect repair via regeneration strategies. In view of delayed bone healing due to local inflammation, herein, pathogenesis‐guided engineering of multi‐bioactive hydrogel therapy is proposed for bone regeneration, by simultaneously improving the osteoimmune environment and enhancing osteogenic differentiation of stem cells. After discovering the pivotal role of persistent inflammation and bone loss in the pathogenesis of periodontitis by transcriptomics, a multi‐bioactive nanotherapy based on self‐assembled nanomicelles (PP5 NMs) is first developed. PP5 NMs effectively rescue osteogenesis of human periodontal ligament cells under pathological conditions and promote bone formation in rats with mandibular or cranial bone defects. By integrating PP5 NMs, a pro‐osteogenic protein rhBMP9, and a hydrogel‐forming temperature‐responsive material, a multifunctional hydrogel therapy is further engineered, which can regulate the pro‐inflammatory/oxidative microenvironment and accelerate bone regeneration. The obtained multi‐bioactive hydrogel capable of co‐delivering and sustainedly releasing PP5 NMs and rhBMP9 displays excellent bone regeneration capability, by synergistic effects of inflammation‐resolving and pro‐osteogenic differentiation of stem cells. Mechanistically, this hydrogel therapy improves the osteoimmune environment by attenuating pathogenesis and enhancing stem cell differentiation via the TLR4/NF‐κB/HO‐1 axis and activating the Smad1/5/8 protein complex. The hydrogel is promising for treating different inflammatory bone diseases.