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 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. 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 Nuclear Factor-kappa B (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.

The present article reviews the emerging role of melatonin (MT) and the Hippo-Yes-associated protein signaling pathway in periodontal regeneration, highlighting their potential to delay the aging process of periodontal ligament stem cells (PDLSCs). Oxidative stress and cellular senescence are major obstacles in regenerative therapies, especially in an aging population. MT, a potent antioxidant, restores the morphology, proliferation, and osteogenic differentiation potential of PDLSCs under oxidative stress conditions. Recent research highlights how MT enhances PDLSC stemness by upregulating Yes-associated protein expression, offering a promising therapeutic strategy to antagonize tissue degeneration. In addition, the article discusses the growing interest in probiotics as a complementary approach to improve oral microbiota and support tissue regeneration. The integration of MT with traditional and novel therapeutic approaches may pave the way for innovative preventive or active treatments in periodontology, aimed at reducing oxidative stress. Future research needs to focus on translating these findings into clinical applications and promoting a deeper understanding of periodontal regeneration and cellular aging.