ReDESigning Hydrogels for Biomedicine: Tuning Transport Control and Biological Functionality in Biocompatible, Antibacterial Eutectogels

ABSTRACT Deep eutectic solvents (DESs) are increasingly explored as functional media for soft biomaterials. Here, two model natural DESs (NADESs), namely reline and glyceline, are shown to modulate gelatin micro‐ and nanostructure, analyte retention, and permeability by forming eutectogels. Time‐resolved cyclic voltammetry in a custom 3D‐printed electrochemical cell enabled reconstruction of permeation profiles and extraction of apparent transport coefficients, uptake rate constants, and diffusion efficiencies. Confocal microscopy and SAXS revealed distinct structural effects: glyceline progressively smoothed surfaces with only minor nanoscale changes, whereas reline induced pronounced network compaction and extreme surface flattening. Using RuHex as an ionic probe, glyceline produced sponge‐like gels with reduced transport efficiency, while reline acted as a kinetic barrier, delaying transport but maintaining stable efficiencies. Importantly, permeation was molecule‐dependent: the hydrogen‐bonding antibiotic ofloxacin permeated more slowly but with higher diffusion efficiency, with glyceline strongly enhancing retention and reline largely preserving throughput. Finally, eutectogels exhibited concentration‐dependent antibacterial activity against Escherichia coli and methicillin‐resistant Staphylococcus aureus and remained cytocompatible toward HaCaT keratinocytes. Overall, NADESs provide a simple strategy to tune transport behavior and emergent biological functionality in gelatin‐based eutectogels, supporting their potential use as controlled, near‐wound drug delivery systems at the skin interface.