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Here, we report a silk\u2010based supramolecular protein delivery platform that addresses these dual physiological barriers. Two phenolic compounds are grafted onto silk sericin (SS), a biocompatible and bioactive natural protein, yielding phenolic SS capable of assembling with protein cargos via supramolecular interactions. To facilitate BBB penetration, the iRGD peptide is incorporated to enable transcytosis via the bystander effect. Phenolic modification alters the ratio of amino to carboxyl groups on SS, thereby tuning its isoelectric point. In acidic lysosomes, the nanocomplex undergoes a surface charge reversal from negative to positive, promoting lysosomal escape and cytosolic release of catalase. In parallel, phenolic SS exhibits intrinsic anti\u2010inflammatory activity, repolarizing activated microglia toward an anti\u2010inflammatory phenotype. In APP\/PS1 transgenic mice, systemic administration of the nanocomplex reduces oxidative stress and neuroinflammation, leading to significant improvements in cognitive function, compared to a non\u2010charge\u2010reversal control. Collectively, this strategy provides a versatile and translatable framework for engineering protein\u2010based nanocarriers to deliver protein therapeutics for neurodegenerative disease treatments.<\/jats:p>","DOI":"10.1002\/advs.75342","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T10:48:25Z","timestamp":1776682105000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dual Physiological Barriers Bypassed by a Silk\u2010Based Supramolecular Protein Delivery Platform for Neuroinflammation Mitigation in Alzheimer's Disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Doudou","family":"Hu","sequence":"first","affiliation":[{"name":"Guangdong Engineering Technology Research Center of Sericulture College of Animal Science South China Agricultural University Guangzhou Guangdong China"},{"name":"State Key Laboratory of Quality Research in Chinese Medicine Institute of 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