A team of researchers has developed a material capable of delivering insulin molecules through the skin. This innovative technology has the potential to transform treatment for type 1 diabetes patients and replace the need for daily injections or pumps.

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Type 1 diabetes is an autoimmune disease in which immune cells attack the pancreatic beta cells that produce insulin. As a result, patients cannot make insulin—the hormone that regulates the entry of glucose into the body’s cells—and therefore must obtain it externally, via injections or a pump [1].
A new study [2] published in Nature proposes a technology that enables the application of an “insulin ointment” containing a unique polymer capable of transporting insulin through the skin layers and into the bloodstream, providing a non-invasive treatment option for people living with diabetes.

Transdermal (i.e., through the skin), non-invasive drug delivery is already used in medicine as an alternative to oral medications or injections, but until now it has been possible only with small molecules because of the skin’s permeability characteristics [3, 4]. The skin, composed of many cellular layers [5], serves as a barrier between the external environment and the internal organs, protecting against disease-causing microbes, and maintaining body temperature and fluid balance. Even when uninjured, this barrier is not hermetic: it allows the passage of small molecules and substances with certain properties. A familiar example is nicotine patches for smoking cessation. There are also patches for administering hormones, opioid drugs, and more. All the molecules that penetrate the bloodstream share two traits: they are small and hydrophobic ("water-repelling") [6]—properties that enable them to cross the skin barrier.

In the new study, researchers employed a unique mechanism based on a polymer called the polyzwitterion poly OP, which they connected to insulin. This polymer is hydrophilic (“water-loving”—the opposite of hydrophobic) and its electric charge can change according to the acidity of its environment. The polymer consists of basic and acidic groups that include positive and negative ions. At neutral pH, these ions balance the polymer’s overall charge. In an acidic environment, H⁺ ions from the acid bind to O^- ions in the polymer, making its overall charge positive [7, 8].

So how does the ointment work? Different skin layers have different pH levels: the outermost layer is more acidic (pH 5), whereas the inner layers are nearly neutral (~7) [9]. When the polymer encounters the acidic outer layer, it acquires a positive charge. This enables it to bind to negatively charged subcutaneous fatty acids and accumulate at the application site. The accumulation allows the polymer to detach from the fatty acids and continue diffusing into deeper skin layers. As it moves inward, its charge becomes neutral—an attribute that helps it slip between skin cells. In the deeper layers, the polymer enters lymphatic capillaries that drain into the bloodstream. From there, the insulin attached to the polymer reaches the cells that need it and facilitates glucose uptake. In this way, the polymer behaves like a chameleon that changes its color to match its surroundings, allowing it to evade obstacles on its way to the target.

The investigators tested the smart-polymer insulin ointment in diabetic mice. After the ointment was applied, blood glucose levels returned to normal values within an hour of a meal. The polymer accumulated mainly in the liver, muscles, and fat tissue, which are key organs in glucose regulation, and the polymer-insulin did not interfere with insulin’s ability to bind its receptor and function. Remarkably, the effect persisted for 12 hours—longer than is achieved with current injectable formulations.

Encouraged by these results, the researchers evaluated the ointment in minipigs, whose skin structure and thickness closely resembles that of humans. The insulin concentration in the ointment was adjusted to therapeutic levels in humans, and once again blood glucose remained stable and normal for 12 hours. Importantly, no adverse skin reactions, such as itching, inflammation, or changes in skin properties, were observed, indicating its potential safety for daily use.

Beyond diabetes care, this technology could potentially enable transdermal delivery of other large biomolecules, replacing treatments that currently require injections. The system would allow drugs to be administered as a ointment or therapeutic patch, sparing patients from injections or the need to continuously wear a pump, and eliminating the stress associated with needles. The researchers’ innovative approach focuses on understanding the properties of the different skin layers in order to design a polymer that can adjust its charge to the environment and thereby pass the skin barrier.

Before we rush to the pharmacy to purchase ointment-based medications, the next step toward making the insulin ointment an available treatment will be clinical trials to confirm its safety and efficacy. This is a lengthy process, and formal approval will take time. Meanwhile, the results in laboratory animals are promising, and if and when such a solution is approved it could be life-changing for more than 500 million people living with diabetes worldwide.

Hebrew editing: Smadar Raban
English editing: Elee Shimshoni

References:

1. 1. Overview of Type 1 diabetes
   2. The original study
   3. Medications administered via skin patch
   4. Mechanism of drug delivery through the skin
   5. Post about skin layers and cancer
   6. Post about hydrophobicity
   7. Post exemplifying electric charge in organic molecules
   8. Protein folding and charge
   9. What is skin pH and why does it matter