Dynamic Covalent Peptide-Drug Conjugates Address the Heterogeneity in Alzheimer's Disease Progression

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.