A skin-permeable polymer for non-invasive transdermal insulin delivery
File(s)
Published online version
Author(s)
Type
Journal Article
Abstract
Non-invasive skin permeation is widely used for convenient transdermal delivery of small-molecule therapeutics (less than 500 Da) with appropriate hydrophobicities1. However, it has long been deemed infeasible for large molecules—particularly polymers, proteins and peptides2,3—due to the formidable barrier posed by the skin structure. Here we show that the fast skin-permeable polyzwitterion poly[2-(N-oxide-N,N-dimethylamino)ethyl methacrylate] (OP) can efficiently penetrate the stratum corneum, viable epidermis and dermis into circulation. OP is protonated to be cationic and is therefore enriched in the acidic sebum and paracellular stratum corneum lipids containing fatty acids, and subsequently diffuses through the intercorneocyte lipid lamella. Beneath the stratum corneum, at the normal physiological pH, OP becomes a neutral polyzwitterion, ‘hopping’ on cell membranes, enabling its efficient migration through the epidermis and dermis and ultimately entering dermal lymphatic vessels and systemic circulation. As a result, OP-conjugated insulin efficiently permeates through the skin into the blood circulation; transdermal administration of OP-conjugated insulin at a dose of 116 U kg−1 into mice with type 1 diabetes quickly lowers their blood glucose levels to the normal range, and a transdermal dose of 29 U kg−1 normalizes the blood glucose levels of diabetic minipigs. Thus, the skin-permeable polymer may enable non-invasive transdermal delivery of insulin, relieving patients with diabetes from subcutaneous injections and potentially facilitating patient-friendly use of other protein- and peptide-based therapeutics through transdermal delivery.
Date Issued
2025-12-11
Date Acceptance
2025-10-09
Citation
Nature, 2025, 648 (8094), pp.459-467
ISSN
0028-0836
Publisher
Springer Science and Business Media LLC
Start Page
459
End Page
467
Journal / Book Title
Nature
Volume
648
Issue
8094
Copyright Statement
© The Author(s) 2025 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41261125
PII: 10.1038/s41586-025-09729-x
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2025-11-19