PLXDC2 siRNA-Mediated Intervention Attenuates Microglial Senescence Through cGAS-STING Signaling.
PLXDC2 siRNA-Mediated Intervention Attenuates Microglial Senescence Through cGAS-STING Signaling.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
CN · Author affiliation · country only
Department of Radiology, Affiliated Hospital and Medical School of Nantong University, Nantong, People's Republic of China.Location evidence
Beijing, CN · Author affiliation
Department of Sports Medicine, Peking University Third Hospital, Institute of Sports Medicine of Peking University, Beijing, People's Republic of China.Location evidence
Huai'an, CN · Author affiliation
Department of General Surgery, Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, People's Republic of China.Location evidence
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Original abstract
Parkinson's disease (PD) is driven by neurodegeneration, iron accumulation, and microglial senescence, yet effective therapy is hindered by the blood-brain barrier (BBB). By constructing the largest-to-date single-cell atlas of the human substantia nigra, we identified a marked upregulation of PLXDC2 in PD microglia. Leveraging this finding, we developed a multifunctional biomimetic nanoplatform (HFn-GM@siPLXDC2/DFO/CeO2-NP). This system co-encapsulates the iron chelator deferoxamine and antioxidant CeO2 nanoparticles, carries PLXDC2-targeting siRNA, and features a ferritin-modified microglial membrane coating to enhance BBB penetration and lesion targeting. In vivo, the nanoplatform efficiently traversed the BBB, reducing iron deposition and reactive oxygen species while suppressing microglial inflammation. Crucially, the treatment significantly alleviated dopaminergic neurodegeneration and improved motor performance-including coordination, balance, and endurance in PD mice. Mechanistically, we demonstrate that PLXDC2 contributes to microglial senescence via the cGAS-STING pathway, and its silencing attenuates neuroinflammation and oxidative stress. This study establishes a potent nanotherapeutic strategy integrating microenvironment remodeling with precise gene regulation to mitigate PD progression and alleviate motor deficits.