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To address this issue, we introduce PLGA\u2010S@Gel\u2010SeHA, a microsphere composed of Poly(lactic\u2010co\u2010glycolic acid) (PLGA), gelatin mineralized selenium\u2010doped hydroxyapatite (Gel\u2010SeHA) and STL1267 (S), which target circadian rhythm gene REV\u2010ERBs (nuclear recerptor subfamily 1, group D, NR1D), to maintain inflammatory cytokine homeostasis for alveolar bone repair. Synthesized via iso\u2010density emulsion and microfluidics, the PLGA\u2010S@Gel\u2010SeHA microspheres are of uniform size and porosity, greatly enhancing the cell adhesion and ingrowth. The combination of Gel\u2010SeHA with PLGA provides abundant biomineralization sites and osteogenic activities. Incorporation of STL1267, currently the safest and most effective small molecule compound targeting REV\u2010ERBs, enables sustained release that mitigates the severe fluctuations of inflammatory cytokines under LPS stimulation. Specifically, it reduces the levels of IL\u20106, TNF, and IL\u20101\u03b2 by over 30% at critical circadian time points, thereby restoring their normal rhythmic expression. This promotes macrophage polarization toward anti\u2010inflammatory M2 phenotypes favorable for osteogenesis. In rat alveolar bone defects, these microspheres demonstrate effective inflammation regulation and significant bone regeneration. By targeting circadian rhythm genes to redress the abnormal inflammatory cytokines fluctuations, this approach may provide a feasible anti\u2010inflammatory strategy for bone repair.<\/jats:p>","DOI":"10.1002\/adhm.202500867","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T05:16:37Z","timestamp":1750828597000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Porous Microspheres Loading Small Molecule Targeting REV\u2010ERBs Modulate Inflammatory Cytokines Fluctuations to Promote Periodontal Bone Regeneration"],"prefix":"10.1002","volume":"14","author":[{"given":"Nayun","family":"Li","sequence":"first","affiliation":[{"name":"Department of Stomatology, Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430022 China"},{"name":"School of Stomatology Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 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