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

Clearance of peripheral amyloid-β (Aβ) has been demonstrated to be promising for overcoming the blood–brain barrier (BBB) hurdle to eliminate brain-derived Aβ associated with Alzheimer's disease (AD). Even so, current developed therapeutic assays for clearance of peripheral Aβ 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 Aβ-targeting pentapeptide KLVFF. KLVFF serves as Aβ-specific ligand that works together with erythrocyte membrane to selectively capture Aβ in the blood. Meanwhile, the erythrocyte membrane coating prevents protein coronas formation and thus retains Aβ-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 Aβ-induced membrane oxidative damage, which enables the extended systemic circulation indispensable for adsorbing Aβ. In vivo studies demonstrate that CuxO@EM-K not only reduces Aβ 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 Aβ associated with AD.