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In this work, a peptide\u2010functionalized cellulose derivative (HPC\u2010pet) was synthesized by conjugating hydroxypropyl cellulose (HPC) with the A\u03b2\u2010targeting KLVFFAED peptide (pet). Integrative experimental and theoretical investigations were performed to characterize the efficacy and underlying mechanism of HPC\u2010pet in mitigating amyloid \u2010 \u03b2\u00a0protein\u2010induced endothelial leakage (APEL), as well as to profile its pharmacokinetic behavior. Benefiting from the synergistic effects between HPC matrix and pet moieties, HPC\u2010pet is capable of suppressing A\u03b2 aggregation progression and encapsulating formed A\u03b2 oligomers. In vitro cellular assays suggested that HPC\u2010pet interferes with the binding of A\u03b2 to endothelial junction proteins and mitigates APEL. Computational modeling further analyzed the intermolecular binding patterns among A\u03b2, HPC, and VE\u2010cadherin to elucidate the molecular interaction mechanism. Consistent with in vitro and computational results, HPC\u2010pet can efficiently traverse the BBB and mitigate APEL. Following sustained in vivo delivery of HPC\u2010pet to AD mice, reduced cerebral A\u03b2 plaque burden and improved cognitive function were detected. This strategy safeguards endothelial function from A\u03b2 oligomer\u2010mediated damage, offering a promising candidate for intervening A\u03b2\u2010driven\u00a0AD progression.<\/jats:p>","DOI":"10.1002\/anie.1351374","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T08:14:26Z","timestamp":1783930466000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Peptide\u2010Functionalized Hydroxypropyl Cellulose Mitigates Amyloid\u2010\u03b2 Protein Induced Endothelial Leakiness and Enhances Cognitive Function in Alzheimer's Disease"],"prefix":"10.1002","volume":"65","author":[{"given":"Qi","family":"Ke","sequence":"first","affiliation":[{"name":"College of Chemistry and Chemical Engineering Ministry of Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules Hubei University  Wuhan P. R. 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