# Substituent‐Based Modulation of Self‐Assembly and Immunogenicity of Amphipathic Peptides

## TL;DR

This study explores how chemical changes to peptides affect their self-assembly and immune response, useful for biomedical applications.

## Contribution

The study systematically examines how substituents on benzyl groups influence peptide self-assembly and immunogenicity.

## Key findings

- Subtle chemical modifications on benzyl rings affect fibril formation and molecular packing.
- Electron-donating and withdrawing groups alter immunogenic responses in vitro and in vivo.
- Such modifications offer practical tools for designing tailored peptide nanomaterials.

## Abstract

Self‐assembled peptide‐based biomaterials provide versatile platforms for biomedical uses, featuring customizable physicochemical properties, biocompatibility, and dynamic capabilities. This self‐assembly process is primarily dictated by primary sequence features, such as hydrophobicity, length, and charge, leading to the formation of fibrils and hydrogels. Amphipathic peptides, with alternating polar and hydrophobic residues, are especially effective in forming supramolecular nanofibers stabilized by π–π interactions and hydrogen bonds. Chemical modifications on aromatic side chains are promising for controlling assembly morphology, stability, and biological activity. However, the influence of these substituents on peptide packing and immunogenicity remains relatively unexplored. Herein, we examine the effect of substituents on benzyl groups attached to short amphipathic peptides. By introducing different electron‐donating and withdrawing groups at the para‐position of benzyl rings and modifying the chain length connecting the backbone to the aromatic moiety, we observe notable effects on fibril formation, molecular packing, and immunogenicity both in vitro and in vivo. Our results show that subtle chemical modifications are practical tools for designing tailored peptide nanomaterials with promising potential in vaccine delivery, tissue engineering, and regenerative medicine.

This study systematically investigates how positional and subtle changes, such as substituents on the phenyl ring attached to short amphipathic peptides, influence their self‐assembly, fibril morphology, and immunogenic responses.