Biomimetic elasticity compressed assembly controls rapid intracerebral drug release to reverse microglial dysfunction

The regulation of microglial dysfunction has become increasingly prominent in treatment of Alzheimer's disease (AD). Herein, we develop a scalable polymer-involved biomimetic assembly that responds to intracerebral reactive oxygen species (ROS) for elastic spreading and concentration-dependent drug therapy. Structurally, a polymer of thermally sensitive deformation is selected for hydrophobic loading of curcumin (Cur) and coordinative grafting onto ultrasmall ceria (CeO2) by elastic compression at transition temperature, which is further sealed by self-polymerized dopamine with apolipoprotein decoration to improve intracerebral shuttling. When triggered by ROS in the lesions, burst exposure of Cur and polymer-linked CeO2 (PCeO2) is achieved. The concentrated Cur switches amyloid-β (Aβ)-activated microglia into normal for mobilizing phagocytosis, and CeO2 has sustainable antioxidant capacity to prevent microglial mitochondrial damage after phagocytosis of PCeO2-captured Aβ. After administration, our findings reveal microglia-mediated Aβ clearance, neuroprotection, and ROS elimination in AD mice. Collectively, this biomimetic assembly provides a promising approach in AD treatments.