Hydrogel scaffold encapsulating MSC-Exos and ZIF-8 promotes bone regeneration via coordinating osteogenesis and immunomodulation

The limited bone regeneration and suboptimal immune responses constitute the major challenges in repairing critical-sized bone defects. As an emerging therapeutic modality, mesenchymal stem cell-derived exosomes (MSC-Exos) exhibit promising application prospects in bone regeneration. In this study, the bone-functionalized MSC-Exos are loaded into GelMA hydrogel scaffolds modified with the bone immunomodulator Zeolitic Imidazolate Framework-8 (ZIF-8) for the repair of critical-sized bone defects. The prepared MSC-Exos/ZIF-8@GelMA composite hydrogel demonstrates excellent biocompatibility and favors the adhesion and proliferation of bone marrow mesenchymal stem cells (BMSCs). The sustained release of exosomes and zinc ions endows the composite hydrogel with synergistically enhanced bone regeneration, angiogenesis, and immunomodulation. Specifically, the microRNA-23a-3p within internalized MSC-Exos activates the AKT signaling pathway in BMSCs by targeting the PTEN node and up-regulates the expression of osteogenesis-related markers. Meanwhile, it is demonstrated for the first time that ZIF-8 inhibits the activation of the non-classical NF-κB pathway in RAW264.7 cells under simulated inflammatory conditions, thereby downregulating pro-inflammatory cytokine expression and inducing M2-type polarization. The rat cranial bone defect model demonstrates that the composite hydrogel significantly enhances new bone formation and angiogenesis <i>in vivo</i> and maintains a low level of inflammation. The design of a composite hydrogel featuring synergistic enhancement of osteogenesis and immunomodulation represents a novel strategy for developing bone tissue engineering scaffolds.