Macrophage-Targeted ROS-Responsive Nanoplatform for Coordinated NF-κB and Nrf2 Modulation in Atherosclerosis Therapy

Atherosclerosis (AS) is a progressive cardiovascular disease characterized by arterial plaque formation, macrophage-driven inflammation, and excessive accumulation of reactive oxygen species (ROS). However, current clinical interventions remain limited by restenosis and thrombosis, while conventional pharmacotherapies suffer from poor bioavailability and off-target toxicity, highlighting the urgent need for more effective and targeted therapeutic strategies. To address the need for precise intervention, we engineered a multifunctional liposomal platform (Rh-ManLP@Ce) designed to synergize active targeting capabilities with environment-responsive payload release. Central to this design is the synthesis of DSPE-PEG-Rhein, a modification that not only significantly improves the solubility and stability of Rhein but also enables its seamless integration into the lipid bilayer, serving simultaneously as a structural element and a therapeutic agent. By incorporating ROS-responsive lipids into this carrier backbone, the system is programmed to undergo rapid structural disassembly solely within the high-ROS plaque microenvironment, ensuring drug release is strictly triggered by local pathological conditions. Further refining its specificity, the liposome surface is decorated with mannose ligands to actively target macrophage mannose receptors, culminating in the construction of the final Cerium Oxide (CeO2)-loaded nanotherapeutic system (Rh-ManLP@Ce). In vitro experiments and in vivo model results confirm that Rh-ManLP@Ce exhibits superior responsiveness in high-ROS contexts and is efficiently internalized by macrophages, achieving significant accumulation within atherosclerotic lesions. At the molecular level, the system orchestrates a dual synergistic effect via Rhein inhibiting the inflammatory NF-κB pathway, while the CeO2 concurrently activates the antioxidant Nrf2 pathway. This coordinated action effectively remodels the pathological microenvironment and suppresses foam cell formation, ultimately delaying plaque progression. Consequently, this work presents a robust, precise strategy for managing atherosclerosis, offering broad implications for therapeutic interventions in other diseases driven by oxidative stress and inflammation.