In-situ engineering of a covalent organic framework-based biomimetic nanoplatform for multi-target therapy of Alzheimer's disease.

To address the complex pathology of Alzheimer's disease (AD), including abnormal amyloid-β (Aβ) aggregation, metal ion homeostasis disruption and oxidative stress, we developed an integrated multifunctional nanoplatform. This platform leveraged a covalent organic framework (TD-COF) with intrinsic capabilities for Cu2+ chelation and Aβ inhibition as the carrier. Through in-situ engineering, ultrafine palladium nanoparticles (PdNPs) were anchored to construct a stable, functionally integrated core (Pd-COF). However, due to limitations of nanomaterials such as short half-life and poor brain targeting, we further employed red blood cell (RBC) membrane for biomimetic modification, yielding the final platform Pd-COF-RBC. In vitro experiments demonstrated that Pd-COF-RBC concurrently achieved Cu2+ chelation, Aβ fibrillation inhibition and reactive oxygen species (ROS) scavenging. Notably, the design of Pd-COF also regulated the size and dispersibility of PdNPs, enhancing catalase-like (CAT) activity by 34.7%. In Aβ-induced cellular models, the material effectively alleviated oxidative stress and mitochondrial dysfunction, increasing cell survival by over 78.4%. Further experiments confirmed that Pd-COF-RBC modified with RBC membrane possessed good biocompatibility, long circulation property and brain accumulation capacity. Based on these findings, we evaluated its therapeutic potential in the transgenic AD C. elegans model. The results demonstrated the motor and cognitive functions of the worms were markedly restored, with the average paralysis time prolonged by approximately 37.3% and the chemotactic index recovering to near wild-type levels. Thus, the study has promise for providing experimental evidence for multi-target intervention against the complex pathological network of AD via an integrated strategy of in situ engineering and biomimetic modification.