Next-generation green transdermal platforms: Integrating deep eutectic solvent chemistry with nanotechnology

Abstract

The clinical translation of transdermal drug delivery remains constrained by an inherent trade-off among solubility, stability, and skin permeability, compounded by increasing regulatory pressure to replace toxic, environmentally unsustainable excipients. Deep eutectic solvents (DES) have emerged as a disruptive class of “designer” solvents capable of overcoming these limitations through precisely tunable intermolecular interactions. Beyond exceptional solubilizing capacity, DES stabilize labile small molecules, peptides, and proteins by suppressing crystallization, polymorphism, and chemical degradation, while reversibly reorganizing stratum corneum lipids and keratin networks to enhance skin permeation. A mechanistic understanding derived from thermodynamic analyses, molecular simulations, and spectroscopic evidence reveals that extended hydrogen-bonding networks, activity coefficient suppression, and interfacial restructuring collectively govern DES performance across both hydrophilic and hydrophobic systems. Integration of DES with nanocarriers, including lipid nanoparticles, micelles, eutectogels, nanoemulsions, and polymerized DES-based microneedles, enables synergistic control over drug loading, barrier transport, and sustained release, thereby extending transdermal delivery to macromolecules and complex therapeutics. Although challenges related to toxicity assessment, standardization, and scalable manufacturing remain, emerging evidence indicates that rationally designed DES-nanotechnology platforms can outperform conventional solvents and penetration enhancers while offering improved biocompatibility and environmental sustainability. Together, these advances position DES-enabled nanotechnology as a paradigm shift in transdermal drug delivery, redefining excipients as active, multifunctional components and opening new avenues for patient-centric, sustainable therapeutics.