Spatiotemporal Regulation of the Bone Immune Microenvironment via a ‘Zn2+–quercetin’ Hierarchical Delivery System for Bone Regeneration

The immunoregulation of tissue-engineered bone has emerged as a prominent area for bone defect repair. While this field demonstrates considerable potential, effectively managing relevant factors and maintaining a balanced immune microenvironment in practical applications remain substantial challenges that require resolution. In this study, we tested a novel comprehensive hierarchical delivery system based on the requirements of a natural immune microenvironment for inflammatory factors, to optimize local immune responses through precise regulation of drug release. Quercetin (Que)-loaded zeolite imidazolate framework-8 (ZIF-8) nanoparticles were embedded in gelatin methacrylate (GelMA) to create a drug-release system featuring a Zn2+ shell and quercetin core. In vivo and in vitro studies demonstrated that this dual sustained-release hydrogel-ZIF-8 system can produce low concentrations of Zn2+ at an early stage, resulting in a mild anti-inflammatory effect and proliferation of bone marrow mesenchymal stem cells (BMSCs). Moreover, as inflammation advances, the release of quercetin works synergistically with Zn2+ to enhance anti-inflammatory responses, reconfigure the local microenvironment, and mitigate the inflammatory response that adversely impacts bone health by inhibiting the NF-κB signaling pathway, thereby promoting osteogenic differentiation. This system is pioneering for sequential microenvironment regulation based on its diverse anti-inflammatory properties, offering a novel and comprehensive strategy for bone immune regulation in the clinical treatment of bone defects.