Dual Physiological Barriers Bypassed by a Silk‐Based Supramolecular Protein Delivery Platform for Neuroinflammation Mitigation in Alzheimer's Disease

ABSTRACT Delivering protein therapeutics to the brain through nanocarriers requires overcoming both the blood‐brain barrier (BBB) and intracellular lysosomal degradation. Here, we report a silk‐based 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‐inflammatory activity, repolarizing activated microglia toward an anti‐inflammatory 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‐charge‐reversal control. Collectively, this strategy provides a versatile and translatable framework for engineering protein‐based nanocarriers to deliver protein therapeutics for neurodegenerative disease treatments.