Intelligent nanoliposome ameliorate chronic intermittent hypoxia-mediated neuronal injury via a dual regulation microglial inflammation strategy

The etiology of obstructive sleep apnea syndrome (OSAS)-associated cognitive dysfunction is unclear and complex. There is growing evidence demonstrate that hyper-activated neuroinflammation, M1 phenotypic microglia polarization, and subsequent neuronal inflammatory damage induced by chronic intermittent hypoxia (CIH) pose a crucial role in OSAS-related cognitive dysfunction. However, the regulatory mechanisms remain unclear, and during treatment, there are inevitable issues with small molecule drugs such as hydrophobicity, lack of targeting, and uncontrolled dosages, especially their inability to cross the blood-brain barrier (BBB), which severely hinders the treatment of CIH related cognitive dysfunction. Herein, a "dual regulation" microglial inflammation strategy was proposed using intelligent nanoliposomes (Ang-Lip@BAY/GW1929), capable of simultaneously regulating PPARγ signaling and IκBα/p65 pathway to reverse the inflammatory microglia transformation. The cationic Ang-Lip@BAY/GW1929 was innovatively used for the dual-targeted identification of CIH-activated microglia that highly express LRP-1 and carry a negative surface charge, to achieve efficient delivery and release of drugs. Simultaneously, PPARγ agonist (GW1929), and IκBα phosphorylation inhibitor (BAY) were delivered from ROS-responsive Ang-Lip@BAY/GW1929 to coordinate the inhibition of NF-κB pathway through PPARγ and IκBα/p65 signaling to systemically regulate microglial polarization, neuroinflammation, neuronal damage, and cognitive dysfunction. Collectively, the study proposed strategies for building bio-targeted liposome-based nanovector to relieve CIH-induced neuron injury, and systematically described treatment mechanisms on CIH related impairment, opening a new path for the treatment of CIH related cognitive dysfunction.