Experimental and Computational Study of Injectable Iron(III)/Ultrashort Peptide Hydrogels: A Candidate for Ferroptosis‐Induced Treatment of Bacterial Infections

Injectable hydrogels are promising candidates as local drug delivery platforms for the treatment of infected wounds. Self-assembled small peptide hydrogels are of interest due to their high biocompatibility, degradability, and ease of synthesis. This study describes the formation of an injectable hydrogel based on the self-assembly of Fmoc-FFpY (Fmoc: fluorenylmethoxycarbonyl, F: phenylalanine, pY: tyrosine phosphate) triggered by electrostatic interactions in the presence of Fe³⁺ ions. Stabilized by H bonding and π-π stacking, the hydrogels exhibit high mechanical stiffness with a <i>G</i>' (storage modulus) of ≈8000 Pa and a self-recovery up to <i>G</i>' ≈100 Pa. Peptide self-assembly yields β-sheets twisted into fibrillar helices of 12 nm in diameter and pitch. Molecular dynamics simulations confirm 1) the aggregation of Fmoc-FFpY in the presence of Fe³⁺ and the adopted secondary structure and show that 2) the aggregated Fmoc-FFpY/Fe³⁺ disrupts the bacterial membrane of <i>Staphylococcus aureus</i> and <i>Pseudomonas aeruginosa</i>, favoring the passive entry of Fe³⁺ into the pathogen. In full agreement with the simulations, the hydrogels exhibit antibacterial activity against both bacteria, likely due to the increased Fe³⁺ entry into the cell, resulting in enhanced production of reactive oxygen species. This work paves the way for ferroptosis-inducing treatment of bacterial infections using injectable ultrashort peptides.