Protein-based medicines have transformed the treatment of many diseases, but they often come with a limitation: they must be injected, sometimes repeatedly, because they are rapidly cleared from the bloodstream. For patients who depend on long-term or lifelong treatment, frequent injections place a considerable burden on everyday life.
Now, researchers from the University of Oslo and Oslo University Hospital, together with international collaborators, have developed an approach to make a therapeutic protein last longer in the body while also opening the possibility of delivering it across mucosal surfaces without the use of needles.
The researchers used human erythropoietin (EPO), a hormone that stimulates the production of red blood cells and is widely used to treat anemia, as a relevant model therapeutic protein. By genetically fusing EPO to an engineered form of human albumin, they designed a long-acting molecule that remained biologically active and showed improved persistence in circulation.
Importantly, the engineered EPO-albumin fusion protein could also be transported across mucosal barriers following non-invasive administration through the nose in humanized mice.
“ This study shows how an understanding of the fundamental biology that regulates albumin homeostasis can be used to design engineered albumin-fused biologics with tailored transport properties ,” says Professor Jan Terje Andersen, who led the study at the University of Oslo and Oslo University Hospital.
“ Instead of only focusing on the therapeutic protein itself, we have engineered its carrier. By doing so, we can control how long the fusion protein stays in the circulation and, at the same time, improve its ability to cross selective biological barriers .”, he adds.
Albumin normally circulates for around three weeks because it binds to a receptor called the neonatal Fc receptor, or FcRn. Inside cells, FcRn rescues albumin from degradation and returns it to the circulation via a pH dependent mechanism.
The researchers have previously reported on characterization of an engineered human albumin variant, (E505Q/T527M/K573P; QMP), which interacts more efficiently with human FcRn. Importantly, fusion to QMP limits antibody fragments from crossing the placenta during pregnancy.
In the new study, EPO was genetically fused to this engineered albumin to determine whether the natural recycling and transport functions of FcRn could be exploited to improve the properties of the therapeutic protein.
The results were striking. When administered intravenously to mice engineered to express human FcRn, EPO fused to engineered albumin showed a plasma half-life of 5.7 days, compared with 1.1 days when EPO was fused to normal human albumin – a more than fivefold improvement.
The engineered EPO-albumin fusion could be detected in the circulation for up to 27 days, whereas the corresponding fusion with normal albumin was no longer detectable after 10 days.
Crucially, extending its persistence did not compromise the therapeutic function of EPO. The engineered fusion bound the EPO receptor with similar strength to a commercially available long-acting EPO product and efficiently stimulated the production of red blood cells.
Following a single intravenous dose, both molecules initially increased red blood cell numbers. However, the effect of the commercial EPO product subsequently declined, whereas animals receiving the engineered EPO-albumin fusion maintained elevated levels for longer.
The researchers then asked whether engineered albumin could act as a molecular carrier to transport EPO across mucosal barriers, and indeed, five times more of the QMP-containing albumin EPO fusion was shown to reach blood than the corresponding fusion containing normal albumin. Most importantly, the protein remained functional after crossing the mucosal barrier, where a stronger and more prolonged increase in red blood cells was measured compared with to a commercially available EPO product used for comparison.
“ The combination of long circulatory half-life and improved ability to cross mucosal barriers is particularly exiting. Protein medicines are normally injected because they do not readily cross the body's barriers. Our results show that we can use QMP and its receptor, FcRn, as a transport system. This could potentially contribute to protein-based medicines that can be given less frequently - and perhaps, for some applications, without needles, ” says Professor Jan Terje Andersen
Funding
The research was partially supported by the Research Council of Norway through its Centres of Excellence scheme and additional grants, as well as by the Novo Nordisk Foundation Distinguished Innovator Grant.
Publication
Anthi, A.K., Bejan, D., Mester, S., Bethur, N., Gonzalo-Gil, E., Benjakul, S., Aaen, K.H., Schlothauer, T., Sandlie, I. & Andersen, J.T. A human erythropoietin-albumin fusion protein tailored for enhanced plasma half-life and delivery across mucosal surfaces. Nature Communications, online 28 October 2026, 10.1038/s41467-026-78243-z.
Nature Communications
Experimental study
Animals
A human erythropoietin-albumin fusion protein tailored for enhanced plasma half-life and delivery across mucosal surfaces.
28-Oct-2026