Nanoflower-Shaped Peptide Assemblies Driven by Serrated β-Sheets and Hydrophobic Interactions for High-Affinity MUC1 Recognition

The transmembrane glycoprotein mucin 1 (MUC1), a glycosylated transmembrane protein, is a clinically valuable tumor marker in various malignant tumors. However, the high fluidity of the cell membrane and the heterogeneity of carbohydrate chain pose difficulties for efficient and stable recognition. Peptide assemblies show significant advantages in target recognition, with enhanced stability and affinity. Herein, we designed a three-motif peptide to take into account both MUC1 targeting and peptide assembly. A peptide library comprising over 10⁸ candidates was synthesized based on “one-bead-one-compound” combinatorial chemistry strategy, and the MUC1-targeted peptide (KLF) was screened with a dissociation constant of ∼10^–8 mol/L. Further mechanism studies revealed that KLF bound to the nonglycosylated dimerization interface of the MUC1 heterodimer. Driven by hydrophobic and β-sheet interactions, KLF self-assembled into flower-shaped nanostructures with the targeting motif exposed on the surface, which showed high affinity and selectivity for MUC1 recognition in various tumor cells. Finally, a drug delivery system based on the KLF assembly was designed and proved effective in tumor therapy in mouse models. This work provides insights into the rational design of peptide assembly systems for targeted recognition and disease therapy.