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

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.