Study Paves Road for Oral Delivery of Proteins

Publication Date: August 5, 2025

This method gets the protein past the intestinal wall.

Summary: The research demonstrates a novel approach using a bacterial product to bypass the intestinal wall, aiming to deliver proteins directly into the bloodstream. The goal is to eventually replace injectable medications with oral pills, although significant refinements are still necessary.

Getting Rid of the Needle

Protein-based treatments are notably effective; however, their oral administration is currently unfeasible due to protein degradation by the gastrointestinal system. Traditionally, these therapies, including antibodies, hormones, and peptides, are delivered through injections, which can be inconvenient and painful. A recent study from the University of Bath, published in the Journal of Controlled Release, reveals a compelling potential solution.

The research team harnessed the cell-penetrating properties of cholix (Chx), a toxin from Vibrio cholerae, the bacterium responsible for cholera. By modifying Chx to its first 197 amino acids, they created a non-toxic variant that retains its ability to penetrate gut cells. This modified cholix was linked to human growth hormone (hGH), which is utilized in treating various disorders, including its investigation in the field of longevity [1].

Mechanism of Action

To facilitate the passage of hGH into the bloodstream, the researchers designed the chimera to be cleaved by furin, a protease (protein-cleaving enzyme) abundant in enterocytes, the absorptive cells lining the intestinal villi. The intent was for the chimera to traverse the entire cell to its basal region, where furin would cleave it, allowing hGH to enter the bloodstream.

Using Antibodies for Enhanced Delivery

The initial Chx-hGH chimeras faced challenges, as they were rapidly cleaved by furin soon after arriving in enterocytes, resulting in reduced bioavailability. To address this, the researchers incorporated a domain from human IgG1 antibodies known as CH2 into the chimera. This modification allowed the chimera to be directed towards alternative pathways within the cell.

By integrating the CH2 domain, the chimeras experienced a significant increase in successful transportation across the enterocyte, ultimately reducing the cleavage occurrences at the apical end (the side facing the intestinal lumen). Instead, the chimeras tended to reach their intended destination at the basal end. Ultimately, this redesign resulted in a more efficient delivery mechanism, with the CH2 domain acting as a ‘swipe-badge’ that facilitated entry into specialized areas within the cell.

Results and Implications

With the aid of these modifications, the research team demonstrated that their best-performing chimera could deliver approximately 4% of the administered dose into the bloodstream of rat models, a remarkably high figure for pre-clinical protein studies, paving the way for future therapeutics.

“This pathway is well understood and has been derived from events in the human intestine, so we know it will work in patients,” stated Professor Randy Mrsny from the University of Bath. “Unlike previous systems, our method doesn’t damage the epithelium and can generically transport a large range of medications, including hormones and cancer treatments that can currently only be injected.”

Challenges Ahead

Despite the promising findings, there are important caveats to consider:

• Delivery Method: The successful delivery observed in rats was conducted via direct injection into specific intestinal segments, isolating them while blocking the remainder of the gut. This approach indicated that absorption in the ileum (the last section of the small intestine) was significantly higher compared to other sections.
• Long-Term Effects: The study did not explore the formation of antibodies or immune activation that might arise from repeated exposure to the bacterial protein or CH2 tags. Concerns around receptor saturation in the ileum and potential effects on gut barrier integrity remain unaddressed.

Despite these challenges, the researchers remain optimistic. “While it’s not the first system to replace injections, ours is the first platform to work safely and consistently, delivering the drug at effective doses and employing a well-understood pathway,” Mrsny added. “Once it’s been developed into a pill, our system would provide a more convenient option for patients.”

Literature

[1] Taverner, A., et al. (2025). Human Fc CH2 domain modifies cholix transcytosis pathway to facilitate efficient oral therapeutic protein delivery. Journal of Controlled Release, 113964.
[2] Fernández-Garza, L. E., et al. (2025). Growth hormone and aging: a clinical review. Frontiers in Aging, 6, 1549453.
[3] Ying, T., et al. (2015). Engineered antibody domains with significantly increased transcytosis and half-life in macaques mediated by FcRn. MAbs, 7(5), 922-930.

About the author: Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span areas from politics to science and philosophy. With a background in economics and international relations, he is particularly intrigued by the social dimensions of longevity and life extension.