News release

From: Springer Nature

Engineered parasite could deliver therapeutic proteins

A method to engineer the parasite Toxoplasma gondii to deliver therapeutic proteins to host neurons across the blood–brain barrier using a mouse model is reported in Nature Microbiology. The findings could enable the development of alternative approaches for therapeutic protein delivery.

Proteins can be used as therapies or as tools to study biological processes. However, their delivery to target cells and tissues is complicated by their large size, interactions with the host immune system and the need to bypass different barriers, such as the blood–brain barrier. T. gondii is a parasite that naturally travels from the human gut to the central nervous system. Previous work has demonstrated that T. gondii can deliver proteins to host cells, but whether this parasite could be engineered to deliver multiple, large therapeutic proteins is unclear.

Shahar Bracha and colleagues developed a strategy to use the two secretory organelles (specialised structures that perform jobs inside a cell) of T. gondii — the rhoptries and dense granules — to deliver proteins into host cells. They selected proteins located in the parasite’s organelles and fused them to different proteins that are known to treat human neurological conditions. The authors successfully demonstrated via laboratory experiments that the proteins could be delivered from both secretory organelles to neurons at the same time.

As proof of concept, they show that a therapeutic protein, MeCP2, used to treat Rett syndrome (a rare neurological disorder that impacts brain development) could be delivered to neurons, bind target DNA and alter host gene expression in cells and in neuron and brain organoids. Bracha and colleagues also show that engineered T. gondii can deliver MeCP2 to neurons in mice with few parasites detected outside the target delivery site and no significant inflammation following delivery.

The authors conclude that although the findings could enable new approaches for therapeutic protein delivery, further research is needed to understand the potential limitations, including efficacy and safety.