Construction of ROS-responsive cascade-targeted liposomes and investigation of their anti-AD effects

Oxidative stress is considered a critical factor in the pathogenesis of Alzheimer's disease (AD). The interaction between oxidative stress and neuroinflammation is closely associated with the production of beta-amyloid (Aβ). Although many drugs exhibit potent anti-inflammatory and antioxidant properties, their poor water solubility and limited ability to penetrate the blood-brain barrier (BBB) often result in reduced efficacy, making accurate AD treatment challenging. Previous studies have shown that borneol (Bor) can enhance BBB permeability, while the MG1 peptide can specifically target M1-type microglial cells. In this study, we constructed reactive oxygen species (ROS)-responsive cascade-targeting liposomes (ROS@Res-Lip) using DSPE-PEG₂₀₀₀-MG1 and DSPE-TK-PEG₂₀₀₀-Bor co-modification. This design aimed to reduce ROS accumulation and enhance BBB penetration by incorporating ROS-responsive thioketal (TK) bonds and Bor, while leveraging the MG1 peptide to improve the targeting of resveratrol (Res) to M1-type microglia. As a result, the drug concentration in the brain was significantly increased, thereby improving therapeutic efficacy. Our findings demonstrate that ROS@Res-Lip can achieve anti-inflammatory, antioxidant, and neuroprotective effects by targeting M1-type microglia and promoting the conversion of M1-type microglia to M2-type microglia.