Harnessing Cross-strand π–π Interlocking for Synergistic Enhancement of Immune Checkpoint Blocking and Ferroptosis

Abstract

The dynamic nature of noncovalent bonds in peptide self-assembly allows for selective accommodation of guest molecules. However, it remains unclear how to harness coassembly to reinforce the host peptides and simultaneously improve the application defects of guest molecules. This study aims to achieve supramolecular synergy between the host and guest, further expanding the functional space of the hybrid nanostructures. Herein, we utilized the aromatic regions present in β-sheet peptides to accommodate aromatic molecules, forming long-range nanotubes (NQ40@AIF) through a unique ‘cross-strand π–π interlocking’. This strategy not only stabilizes the coassembly effectively but also synergizes the biological functions of the host and guest molecules. Moreover, due to the chemical diversity of the coassembled NQ40@AIF, it exhibits advantages in tumor combination therapy, achieving effective synergy between ferroptosis and immune checkpoint blocking. This work provides a minimalistic strategy for constructing peptide nanostructures with complex functionalities.