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Pongsigeraxi Borjigin,1 Caixia Deng,2 Rilaga Su,2 Juan Li,1 Ying Ying,3 Yingsong Chen,4 Tegexibaiyin Wang5 1College of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao, Inner Mongolia Autonomous Region, People’s Republic of China; 2College of Mongolian Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, People’s Republic of China; 3College of Chemical Materials, Inner Mongolia Minzu University, Tongliao, Inner Mongolia Autonomous Region, People’s Republic of China; 4National and Local Joint Mongolian Medicine R&D Engineering Center, Inner Mongolia Minzu University, Tongliao, Inner Mongolia Autonomous Region, People’s Republic of China; 5Affiliated Hospital, Inner Mongolia Minzu University, Tongliao, Inner Mongolia Autonomous Region, People’s Republic of ChinaCorrespondence: Yingsong Chen, National and Local Joint Mongolian Medicine R&D Engineering Center, Inner Mongolia Minzu University, Tongliao, Inner Mongolia Autonomous Region, 028000, People’s Republic of China, Email Cys1979@126.com Tegexibaiyin Wang, Affiliated Hospital, Inner Mongolia Minzu University, Tongliao, Inner Mongolia Autonomous Region, 028000, People’s Republic of China, Email tegexibaiyin@yeah.netPurpose: This study aimed to enzymatically synthesize pearl powder fluorescent carbon dots (PFCDs) and investigate their neuroprotective potential against cerebral ischemia/reperfusion injury (CIRI) by modulating the Anxa2/NF-κB signaling pathway.Methods: PFCDs were synthesized through enzymatic digestion and characterized. Neuroprotective effects were assessed using an in vitro oxygen–glucose deprivation/reoxygenation (OGD/R) model in PC12 cells and a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model. Cell viability, neurological function, cerebral infarct volume, and neuronal injury were evaluated. Expression of Anxa2/NF-κB signaling pathway proteins and inflammatory cytokines (TNF-α, IL-6, IL-1β) was analyzed by Western blot, immunofluorescence, and ELISA.Results: The synthesized PFCDs exhibited an organic–inorganic hybrid structure, uniform particle size below 10 nm, and distinctive optical properties. In vitro, PFCDs enhanced cell viability under OGD/R conditions, inhibited phosphorylation of Anxa2 and NF-κB p65, and reduced secretion of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). In vivo, treatment with PFCDs in MCAO/R rats improved neurological function, reduced cerebral infarct volume, and alleviated neuronal injury. These protective effects were linked to downregulation of the Anxa2/NF-κB signaling pathway and reduced serum levels of inflammatory cytokines.Conclusion: We successfully achieved the enzymatic synthesis of carbon dots from pearl powder, characterized by a unique organic–inorganic hybrid structure. PFCDs effectively alleviated CIRI-induced neuroinflammation by suppressing the Anxa2/NF-κB signaling pathway, highlighting their therapeutic potential as a nanomedicine derived from natural products. Keywords: pearl powder fluorescent carbon dots, cerebral ischemia/reperfusion, oxygen–glucose deprivation/reoxygenation, middle cerebral artery occlusion/reperfusion, neuroinflammation, Anxa2/NF-κB signaling pathway