Dynamic Covalent Peptide‐Drug Conjugates Address the Heterogeneity in Alzheimer's Disease Progression
Abstract
ABSTRACT A growing understanding of the pathophysiological evolution of Alzheimer's disease (AD) underscores the heterogeneity in its progression as a critical factor undermining the success of various candidate interventions and complicating the establishment of effective pharmacotherapeutic regimens. Here, we introduce the development of a hierarchical‐responsive therapeutic agent self‐assembled from phenylboronate ester‐linked Tjernberg's KLVFF peptide‐curcumin conjugates (CPKNAs), which is designed to dynamically track the spatiotemporal coordinates of biomarkers associated with AD heterogeneity in progression. The dynamic covalent phenylboronate ester bond undergoes varying degrees of dissociation in response to the temporal evolution patterns of amyloid‐β, reactive oxygen species, and glucose, three key indicators for staging AD progression, enabling self‐adaptive regulation of drug distribution and dosing tailored to specific phenotypes. Employing seven cellular models and three types of transgenic mice simulating different AD stages, we demonstrate that CPKNAs effectively minimize the risks of under‐ or overtreatment, achieving consistent therapeutic outcomes in mitigating cellular damage and improving brain dysfunction.
Article Details
Authors (13)
Yuheng Yang
New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry
Ting Wu
Children’s Hospital, Zhejiang University School of Medicine
Xuan Fan
Yuhang Yao
New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry
Chen Chen
Kun Kang
New Cornerstone Science Laboratory MOE Key Laboratory For Analytical Science of Food Safety and Biology College of Chemistry Fuzhou University Fuzhou China
Xianzhe Tang
New Cornerstone Science Laboratory MOE Key Laboratory For Analytical Science of Food Safety and Biology College of Chemistry Fuzhou University Fuzhou China
Tingjing Huang
State Key Laboratory of Biomedical Imaging Science and System Paul C. Lauterbur Research Center for Biomedical Imaging Institute of Biomedical and Health Engineering Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen China
Yixuan Xu
Department of Chemistry
Yu He
Department of Cardiovascular Surgery, Med-X Institute, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China.
Zhitong Chen
Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology
Zhaowei Chen
New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry
Huanghao Yang
New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry