The study identified phage surface proteins acting as molecular anchors. These proteins confer phages ith the ability to attach to human cells. Using genetic engineering, the researchers transferred these adhesion proteins onto the surface of another phage that otherwise lacked this ability. The engineered phages then bound more efficiently to human cells, entered them at higher rates, and remained in the mouse gastrointestinal tract for an extended period, whereas the non-engineered phages cleared rapidly.
This shows that epithelial binding is not merely a curious side effect but instead an evolutionarily advantageous strategy driven by modular phage surface proteins.
“Phages are famous for attacking bacteria, but they may have more to offer than antibacterial activity alone. Our study shows that some phages carry molecular anchors that help them attach to human cells and even enter them. They are not human viruses and cannot replicate in human cells, but this unusual ability could one day be used to design more precise phage-based therapeutics,” said Gábor Apjok , co-first and co-corresponding author of the study.
Microscopy-based image analysis played an important role in the work. The researchers not only visualized phages entering cells, but also observed that they preferentially traffic to the Golgi apparatus and the endoplasmic reticulum, two main cell organelles implicated in numerous disorders. The pathways leading to these compartments are non-degradative, suggesting that phages taking this scenic route might still be intact, unlike those that are taken up by degradative processes e.g. through lysosomes.
The study also raises new questions, including if and how long internalized phages remain intact inside cells, whether this process affects cellular functions or ultimately influences physiological processes, and whether it can be harnessed for therapeutic delivery.
The work also reshapes how we think about the gut microbiome. The intestine is not only a bacterial ecosystem but also one of the most virus-rich environments in the human body. These results suggest that some phages may interact not only with bacteria but also directly with the epithelial surface of the gut.
“In the gut, phages do not move through empty space: they have to persist within a complex environment of mucus, bacteria, and epithelial cells. Our results suggest that certain surface proteins may help them not only pass through this environment, but also attach to it. This is an important step toward understanding how the gut virome is organized.” said Tóbiás Sári , co-first author of the study.
The researchers also found that phages carrying similar adhesion-related genes are not rare exceptions. They occur in several common gut phage groups that are among the most abundant and prevalent members of the gut virome, suggesting that these molecular anchors may help explain their ecological success. Phages carrying such genes also appeared to be more abundant in healthy gut viromes. This does not mean that they are drivers of health; rather, they may be better adapted to persist in a stable, well-functioning mucosal environment.
The findings may also be relevant for the future of phage therapy. For a therapeutic phage to kill the target bacterium, it also has to reach the right location and remain there long enough to act. Understanding which proteins control phage binding to human tissues could help design phages with more precise targeting and retention properties.
The work was led by the Bálint Kintses lab at the HUN-REN Biological Research Centre, Szeged , and involved contributions from multiple laboratories and disciplines, including microscopy, phage biology, bioinformatics, microbial genomics, and bioengineering.
The paper is available here: https://www.nature.com/articles/s41467-026-74031-x
Nature Communications
Experimental study
Cells
Prevalent gut phages encode modular adhesins mediating epithelial binding and endoplasmic reticulum trafficking
4-Jun-2026