Reverse Micelles: The Gateway for Oral (Poly)Peptide Delivery

Reverse micelles (RM) have played a central role in biotechnology, yet their pharmaceutical use has been constrained by instability, high water content and non-biocompatible surfactants. Classical wet RM (wRM) contain a discrete aqueous core whose size and solubilization behavior are governed by surfactant packing, hydration level and physicochemical properties of the hydrophobic phase. Although these systems provided insights into nanoconfined environments, their sensitivity to dilution and environment has limited translation into drug delivery. Recent developments renew interest in dry RM (dRM), which reduce internal water to below 1% and rely mainly on interfacial rather than bulk-like water domains, with electrostatic and non-covalent interactions contributing to stabilization of highly hydrophilic (poly)peptides (pP). dRMs expand the application space for pP therapeutics, supporting delivery routes requiring low hydration and robust microenvironments. This review integrates RM architecture and outlines performance criteria for oral pP delivery, including high loading capacity, increased pP lipophilicity, protection from enzymatic degradation, enhanced epithelial permeation and favorable safety. In vivo studies demonstrate that dRM achieve comparable or improved oral bioavailability relative to hydrophobic ion pairs or wRM in selected systems, underscoring why RM remain relevant and why maintaining minimal hydration and formulation flexibility are central to unlocking their therapeutic potential.