Researchers at the University of Oslo have genetically fused erythropoietin to an engineered variant of human albumin, extending its plasma half-life more than fivefold in mice and enabling successful non-invasive delivery across mucosal barriers without relying on injections.
Protein-based medications have fundamentally reshaped modern therapeutics, yet they carry a persistent drawback because they are rapidly cleared from the bloodstream, requiring patients to undergo frequent injections. Regular needle pricks create a significant lifestyle challenge for individuals who require continuous or lifelong medical care.
Engineering the Albumin Carrier for Extended Circulation
Building on previous work characterizing an engineered human albumin variant designated as QMP—which features specific alterations including E505Q, T527M, and K573P—the researchers genetically fused human erythropoietin to this engineered protein.
To serve as a suitable test therapeutic, the team selected human erythropoietin—a well-established hormone that drives red blood cell generation and serves as a standard treatment for anemia. Through the genetic attachment of EPO to a modified human albumin molecule, the team created a durable therapeutic agent that retained its biological function while lasting much longer in the bloodstream. When tested in mice engineered to express human FcRn, the engineered fusion protein achieved a plasma half-life of 5.7 days versus just 1.1 days when EPO was fused to normal human albumin.
Intranasal Delivery Increases Red Blood Cell Levels
Crucially, extending its persistence did not compromise the therapeutic function of EPO.
In experiments examining whether the modified albumin could carry EPO through mucosal surfaces, the investigators discovered that intranasal administration in mice delivered fivefold greater levels of the engineered fusion protein into the bloodstream compared to standard albumin. This transport mechanism yielded a more potent and extended elevation in red blood cells than what was achieved using standard commercial EPO treatments.
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.
Implications for Future Protein Therapeutics
The findings point toward a shift in how protein-based drugs are designed, focusing adjustments on the molecular carrier rather than the therapeutic protein itself.
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.
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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.
The study, titled A human erythropoietin-albumin fusion protein tailored for enhanced plasma half-life and delivery across mucosal surfaces, was detailed in Nature Communications by lead author Aina K. Anthi and colleagues. Investigators note that exploiting FcRn and QMP as an active transport system could eventually allow certain protein medications to be administered much less frequently or, for specific applications, entirely without needles.