Peptide‐Functionalized Hydroxypropyl Cellulose Mitigates Amyloid‐β Protein Induced Endothelial Leakiness and Enhances Cognitive Function in Alzheimer's Disease

Amyloid‐β (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis by inducing endothelial leakiness and disrupting blood–brain barrier (BBB) integrity via direct binding to endothelial tight junction proteins. In this work, a peptide‐functionalized cellulose derivative (HPC‐pet) was synthesized by conjugating hydroxypropyl cellulose (HPC) with the Aβ‐targeting KLVFFAED peptide (pet). Integrative experimental and theoretical investigations were performed to characterize the efficacy and underlying mechanism of HPC‐pet in mitigating amyloid ‐ β protein‐induced endothelial leakage (APEL), as well as to profile its pharmacokinetic behavior. Benefiting from the synergistic effects between HPC matrix and pet moieties, HPC‐pet is capable of suppressing Aβ aggregation progression and encapsulating formed Aβ oligomers. In vitro cellular assays suggested that HPC‐pet interferes with the binding of Aβ to endothelial junction proteins and mitigates APEL. Computational modeling further analyzed the intermolecular binding patterns among Aβ, HPC, and VE‐cadherin to elucidate the molecular interaction mechanism. Consistent with in vitro and computational results, HPC‐pet can efficiently traverse the BBB and mitigate APEL. Following sustained in vivo delivery of HPC‐pet to AD mice, reduced cerebral Aβ plaque burden and improved cognitive function were detected. This strategy safeguards endothelial function from Aβ oligomer‐mediated damage, offering a promising candidate for intervening Aβ‐driven AD progression.