PLXDC2 siRNA‐Mediated Intervention Attenuates Microglial Senescence Through cGAS‐STING Signaling

Abstract

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/CeO 2 ‐NP). This system co‐encapsulates the iron chelator deferoxamine and antioxidant CeO 2 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.