Ultrasmall Polymeric Micelles Enable Noninvasive Transdermal Rosiglitazone Delivery via Lipid Fluidization and Transcytosis.

Noninvasive transdermal drug delivery (TDD) offers sustained therapeutic release but is hindered by the stratum corneum (SC) barrier. Herein, we report ultrasmall polymeric micelles (PMs) embedded in poly(vinyl alcohol) hydrogels for the passive TDD of rosiglitazone (RGT) to treat Type 2 diabetes mellitus (T2DM). We synthesized amphiphilic brush copolymers with varied hydrophobic cores (linear alkanes, benzene, borneol) to tune SC interactions and ensure colloidal stability. Ex vivo murine skin studies demonstrated that PM variants with C10 alkane and benzene cores achieved 10.56% and 19.84% cumulative permeation at 24 h, respectively, via dual paracellular/intracellular routes. In vivo, PM hydrogels delivered steady plasma accumulation. In a T2DM model, transdermal RGT reduced blood glucose by 30% over 12 days without observable skin or organ toxicity. This nanoplatform enables noninvasive systemic delivery, offering a robust alternative to oral administration for sustained glycemic control.