Many diabetics need to inject themselves with insulin regularly to keep their blood sugar levels stable. Researchers have long been working on ways to replace syringes with less invasive methods such as plasters. The problem is that our skin forms a tight barrier for large molecules like insulin. But now researchers have overcome this hurdle. To do this, they coupled insulin to a so-called polyzwitterion called OP, which exploits the skin’s changing pH gradient to penetrate different skin layers. In tests, insulin administered in this way passed through the skin barrier of mice and mini pigs and successfully brought their blood sugar levels to the desired level. The study thus opens up new avenues for the development of insulin patches for human diabetics.
Administration through the skin is a convenient, low-threshold way for patients to take medication – be it local painkillers, hormones for contraception or nicotine patches for smoking cessation. All of these active ingredients are so small that they can penetrate the skin. “For a long time, however, this route was considered impossible for large molecules due to the enormous barrier that the skin structure represents,” explains a team led by Qiuyu Wei from Zhejiang University in China. This also applies to insulin, which around 1.8 million people in Germany alone have to inject themselves every day. For many people, the injections are very unpleasant and sometimes even trigger phobias. Researchers have been working on less invasive administration methods for a long time – for example, using plasters that are peppered with tiny microneedles.
Transfer through the skin
Wei and his team have now found a way to deliver insulin through the skin into the bloodstream without the need for needles. The key lies in a so-called polyzwitterion, which has the complicated name Poly[2-(N-Oxid-N,N-Dimethylamino)ethylmethacrylat]OP for short. This OP has a special property: depending on the pH value, it is either neutral, positively or negatively charged. This means it is positively charged in the top layer of skin, which has an acidic pH value. This allows it to interact with the fatty acids of this skin layer and penetrate the first barrier. Below, in the epidermis and dermis, there is a neutral pH value. In this environment, OP is also neutral. “This allows it to ‘hop’ on the cell membranes and efficiently cross the epidermis and dermis,” explain the researchers. “This is how it eventually enters the systemic circulation.”
The highlight: OP can be loaded with other molecules and takes them with it on its journey from the skin surface into the bloodstream. Wei and his colleagues coupled insulin with OP and applied this combination to the skin of diabetic mice and minipigs. In fact, the insulin bound to OP easily passed through the skin barrier and distributed into the bloodstream. It successfully bound to the insulin receptors of the test animals and lowered their blood sugar levels to the normal range within one to two hours – similar to injected insulin.
Effective control of blood sugar
Compared to injected insulin, surgical insulin absorbed through the skin actually offered an advantage: It accumulated in tissues such as the liver, fatty tissue and muscles, all of which play an important role in regulating blood sugar levels. As a result, its effect lasted longer than with injected insulin, as Wei and his team found. The researchers did not observe any undesirable side effects. The animals’ skin also remained undamaged and was not irritated. “The surgical insulin penetrated the skin completely non-invasively and without causing irritation,” reports the research team. “Repeated applications caused no structural changes, no increase in the gaps between cells, and no signs of inflammation or cell death.”
From the researchers’ perspective, their discovery represents a promising way in which insulin can be administered through the skin. “This could free patients with diabetes from subcutaneous injections,” they write. However, before the technique can be used in humans, further studies are required to ensure long-term safety and effectiveness and to enable precise dosage tailored to patients. If the process actually proves to be successful with insulin, it could also be an option for other therapeutic agents that are currently considered too large to penetrate the skin.
Source: Qiuyu Wei (Zhejiang University, China) et al., Nature, doi: 10.1038/s41586-025-09729-x