Boosting Supramolecular Gelation Efficiency and Properties: Ionic Strength as a Key to Superior Hydrogels

Controlling the minimum gelation concentration (MGC) of low molecular weight (LMW) hydrogelators is a key for modulating gel properties, such as mechanical strength, viscoelasticity, and stability, which are crucial for applications ranging from drug delivery to tissue engineering. However, tweaking the MGC under specific conditions, such as pH and/or temperature, poses a considerable challenge. Herein, we varied the ionic strength of buffer solutions using NaCl for several LMW hydrogelators, including Fmoc-Phe, Fmoc-Tyr, Fmoc-Trp, Fmoc-Met, and Fmoc-Cha, and assessed their gelation efficiency at pH 7.4 and ambient temperature. Interestingly, Fmoc-Phe demonstrated a ∼67% (3-fold) MGC reduction, from 0.24 to 0.08 wt %, at 500 mM NaCl, transforming it a "super hydrogelator" (MGC < 0.1 wt %), while Fmoc-Trp showed 60% MGC reduction. Higher ionic strength effectively shields the electrostatic repulsion between negatively charged (-COO^-) groups on the Fmoc-Phe, promoting closer aggregation and more efficient self-assembly and allowing for gelation at lower concentrations. In contrast, Fmoc-Met, Fmoc-Cha, and Fmoc-Tyr precipitated in the presence of NaCl, suggesting that NaCl specifically modulates the MGC of Fmoc-amino acid gelators containing unsubstituted aromatic side chains. Furthermore, these results indicate that cation-π interactions likely play a role, alongside carboxylic acid neutralization. While Fmoc-Phe forms gels in the presence of other monovalent cations, it does not form a hydrogel in the presence of divalent (CaCl₂) and trivalent (AlCl₃), indicating that enhancement of hydrogelation is specific to monovalent cations. Although the fibrillar structure of Fmoc-Phe hydrogels remained consistent, addition of NaCl increased fibril stickiness, creating densely packed networks that modulate the mechanical strength. Unlike typical cases where increased ionic strength leads to precipitation, Fmoc-Phe gelation at high NaCl concentrations (150-500 mM) is significant, yielding a robust supramolecular hydrogel that remains stable in high ionic-strength environments. This outcome suggests that ionic strength could be a valuable factor to enhance the efficient gelation of LMW hydrogelators.