Intranasal liposomes co-delivery of Aβ-targeted KLVFF and ROS-responsive ceria for synergistic therapy of Alzheimer’s disease

β-Amyloid (Aβ) aggregation and oxidative stress are primary pathological features of Alzheimer's disease (AD). Combination therapies that target brain tissue and corporately address these main pathological factors are required for effective AD treatment. Here, we developed a multifunctional liposome delivery system (KLVFF@LIP-CeO2) for co-delivery of Aβ-targeted KLVFF and reactive oxygen species (ROS)-responsive Ceria (CeO2) through intranasal administration. After Aβ1-42-induced ROS and apoptosis in HT22 cells, KLVFF@LIP-CeO2 exhibited significant protective effects by inhibiting Aβ aggregation and scavenging multi-ROS. With these features, we verified the therapeutic effectiveness of KLVFF@LIP-CeO2 in APPswe/PSEN1dE9 (APP/PS1) model mice. After intranasal administration, KLVFF@LIP-CeO2 demonstrated sufficient and rapid accumulation in the brain and significantly alleviated Aβ deposition and oxidative stress, corporately contributing to the rescue of cognitive impairment of APP/PS1 mice. These results highlight the clinical potential of these multi-targeted nanoparticles for synergistic therapy of AD.