Bioactive Glycyrrhizic Acid Ionic Liquid Self‐Assembled Nanomicelles for Enhanced Transdermal Delivery of Anti‐Photoaging Signal Peptides

Abstract Sigal peptides have garnered remarkable efficacy in rejuvenating photoaged skin and delaying senescence. Nevertheless, their low solubility and poor permeability bring about a formidable challenge in their transdermal delivery. To address this challenge, bioactive ionic liquids (ILs) synthesized from natural glycyrrhizic acid (GA) and oxymatrine (OMT) with eminent biocompatibility is first prepared. The components ratios and inherent forming mechanisms of GA‐OMT (GAO) are optimized by molecular dynamics simulations and density functional theory calculations. Remarkably, GAO can significantly improve the sparingly soluble properties of palmitoyl pentapeptide‐4 (PAL‐4), a model peptide drug. Subsequently, GAO self‐assembled micelles loading PAL‐4 (GAO/PAL‐4‐SM) are fabricated without additional auxiliary materials. The permeation and subcutaneous retention of PAL‐4 are significantly promoted with 10wt.% GAO‐SM. Moreover, GAO ILs facilitated PAL‐4 permeation by enhancing its miscibility and interaction with stratum corneum (SC), offering a pulling effect and micellar structures for PAL‐4, as elucidated by computational simulations. In cellular and animal photoaging experiments, GAO/PAL‐4‐SM possessed remarkable capabilities in boosting collagen and hyaluronic acid regeneration, mitigating inflammation and apoptosis, accelerating macrophage M2 polarization, thereby lessening skin wrinkles and leveraging elasticity. Collectively, the research innovatively designed an ILs self‐assembled nano‐micellar transdermal delivery system to enhance the permeability and anti‐photoaging effect of signal peptides.