Engineered choline-Salcaprozate ionic liquids for enhanced non-invasive delivery of macromolecular antidiabetics.

The management of diabetes relies heavily on macromolecular biologics, which are predominantly administered via subcutaneous injection. However, its invasiveness compromises patient compliance and leads to injection-related complications. Among all the clinically attractive alternatives, mucosal administration, while non-invasive and enabling rapid absorption, faces significant challenges from physiological barriers that limit drug permeability. Herein, we engineered a novel choline-salcaprozate ionic liquid (CS-IL) system that could overcome these limitations and enable efficient mucosal delivery of insulin and semaglutide. To evaluate its potential, comprehensive in vitro and in vivo studies were conducted, which revealed that CS-ILs significantly enhanced drug permeability and mucosal retention via both intranasal and sublingual routes, thereby achieving robust hypoglycemic effects comparable to subcutaneous injection. Notably, a key mechanistic insight uncovered that CS-ILs boost paracellular transport via the transient and safe modulation of intercellular junctions. Consequently, with its compelling biocompatibility profile and potent efficacy across mucosal routes, this versatile IL platform emerges as a promising strategy for clinical translation, potentially revolutionizing non-invasive delivery for diabetes therapeutics.