Neuronal damage caused by l3-amyloid (Al3) aggregates and excess reactive oxygen species (ROS) is a crucial pathogenic event in Alzheimer's disease (AD). However, current Al3-targeting RNA interference (RNAi) treat-ments have shown limited therapeutic efficacy due to ineffective intracerebral siRNA delivery and overlooked crosstalk between excess ROS and Al3 aggregates in the brain. Herein, a ROS-responsive nanomodulator (NM/ CM) was developed for the combinational treatment of RNAi and ROS elimination for AD. NM/CM was coated with 4T1 cell membranes, which endowed NM/CM with the capability to cross blood-brain barrier (BBB). After being internalized by neural cells, NM/CM releases curcumin (Cur) and siIFITM3 spontaneously into the cyto-plasm. The released Cur can eliminate ROS, protecting neurons from oxidative damage and reducing the pro-duction of Al3 induced by ROS-related neuroinflammation. The released siIFITM3 can downregulate the expression of interferon-induced transmembrane protein 3 (IFITM3), thereby reducing the abnormal Al3 pro-duction mediated by IFITM3. As a result, NM/CM remarkably alleviated ROS-and Al3 aggregate-induced neurotoxicity in vitro, showing significant neuroprotective effects. This work demonstrates the potential of NM/CM in the development of novel and effective AD combination therapies.