Dual‐Integrin‐Targeted Supramolecular Peptide Nanoarchitectonics for Enhanced Hepatic Delivery and Antifibrotic Therapy

Abstract The integration of integrin‐binding peptides within self‐assembling building blocks is crucial for the development of targeted nanoarchitectonics. However, such constructs typically incorporate only a single integrin‐binding peptide, limiting their multifunctionality. Herein, a rationally designed self‐assembling peptide with dual integrin‐binding motifs for α5β1 and αvβ3 is presented. This peptide forms highly ordered nanofibers or nanoparticles (VH‐NPs) with tailored secondary structures. In vitro and in vivo studies demonstrate that VH‐NPs target activated hepatic stellate cells via dual‐integrin interactions, enabling selective targeting to fibrotic livers and suppressing α5β1 and αvβ3. Notably, VH‐NPs can encapsulate rhein through noncovalent interactions, resulting in peptide‐rhein nanoarchitectonics that display augmented antifibrotic effects. These findings highlight the potential of self‐assembling peptides that leverage multiple targets and therapeutic modules as a promising strategy for constructing multifunctional nanoarchitectonics.