The pH-responsive permeation mechanism of zwitterionic polymers promotes transdermal insulin delivery

The transdermal delivery of macromolecular drugs has long been limited by the barrier effect of the stratum corneum and the underlying active epidermis. A recent study published in Nature proposed a non-invasive transdermal delivery strategy based on poly[2-(N-oxide-N,N-dimethylamino)ethyl methacrylate] (OP). This strategy takes advantage of the pH gradient from the acidic surface to the neutral deep layers of the skin to achieve efficient penetration of OP and OP-insulin through the stratum corneum, active epidermis, and dermis. OP-insulin possesses full-thickness skin permeability, enabling it to penetrate all skin layers and subsequently enter the systemic circulation. It also facilitates intratissue diffusion through membrane surface hopping and intercellular contact transfer. Experiments in mice and minipigs demonstrated that locally administered OP-insulin could rapidly enter the bloodstream and exhibited broad tissue distribution, as evidenced by fluorescence accumulation in organs such as the liver, fat, and muscle. This study showcases the potential of transdermal delivery strategies that combine material chemistry with the characteristics of the skin microenvironment for the non-invasive delivery of macromolecular drugs, offering new therapeutic approaches for diseases such as diabetes.