Self-Protecting Biomimetic Nanozyme for Selective and Synergistic Clearance of Peripheral Amyloid-β in an Alzheimer's Disease Model

Clearance of peripheral amyloid-beta (A beta) has been demonstrated to be promising for overcoming the blood-brain barrier (BBB) hurdle to eliminate brain-derived A beta associated with Alzheimer's disease (AD). Even so, current developed therapeutic assays for clearance of peripheral A beta are still facing challenges on how to avoid interference of certain biological molecules and prevent triggering the activation of immune responses and blood clotting. Here, a biomimetic nanozyme (CuxO@EM-K) with augmented protein adsorption resistance, minimized immunogenicity, and enhanced biocompatibility is designed and synthesized. The CuxO@EM-K is made of CuxO nanozyme wrapped with modified 3xTg-AD mouse erythrocyte membrane with A beta-targeting pentapeptide KLVFF. KLVFF serves as A beta-specific ligand that works together with erythrocyte membrane to selectively capture A beta in the blood. Meanwhile, the erythrocyte membrane coating prevents protein coronas formation and thus retains A beta-targeting ability of CuxO@EM-K in biological fluids. More importantly, the CuxO core with multiple antioxidant enzyme-like activities stabilizes the outer erythrocyte membrane and simultaneously mitigates A beta-induced membrane oxidative damage, which enables the extended systemic circulation indispensable for adsorbing A beta. In vivo studies demonstrate that CuxO@EM-K not only reduces A beta burden in the blood and brain but also ameliorates memory deficits in the widely used 3xTg-AD mouse model. Moreover, CuxO@EM-K shows no apparent toxicity in 3xTg-AD mice. Overall, this work provides an example for developing biocompatible and synergistic clearance of peripheral A beta associated with AD.