Engineered Brain Parasite Used for Therapeutic Delivery

T. gondii is a protozoan that infects nearly all warm-blooded animals. Researchers have manipulated it to deliver therapeutic proteins directly to brain cells. This concept has been tested in lab-grown human brain tissue and living mice, with findings indicating minimal side effects.

The research team, led by neuroscientist Shahar Bracha of the Massachusetts Institute of Technology, demonstrated the use of T. gondii as a delivery system in various cellular environments, including cultured fibroblasts, differentiated neurons, primary neurons, human brain organoids, and in vivo in mice. They characterized factors affecting delivery patterns under different conditions.

The blood-brain barrier is a selective membrane that protects the brain from potentially harmful substances in the bloodstream but also poses a challenge for delivering therapeutic proteins. It prevents nearly all large and hydrophilic molecules, including many therapeutic proteins, from entering the brain.

T. gondii causes toxoplasmosis, which can lead to serious complications in some cases. However, the research team has utilized the parasite's ability to penetrate the blood-brain barrier for therapeutic purposes. By modifying two of the parasite's secretion organelles, the researchers enabled T. gondii to deliver proteins known to treat human neurological conditions.

The engineered T. gondii was tested in lab-grown human brain tissue, known as organoids. The modified parasite delivered MeCP2, a protein used to treat Rett syndrome—a genetic disorder affecting brain development. The delivered protein successfully bound to DNA in the organoids and altered gene expression, indicating effective protein delivery.

3D visualization of group-average distribution of ZsGreen+ cells within the whole brain, indicating where the therapeutic proteins are being delivered (Bracha et al., Nat. Microbiol., 2024)

Further tests in living mice showed that the engineered T. gondii infected the hosts and delivered MeCP2 with minimal inflammation, comparable to control groups exposed to non-edited microbes and saline.

Approximately 25 to 30 percent of the global population carries T. gondii asymptomatically. The researchers suggest that this characteristic could be repurposed for therapeutic use. They noted that neurons are particularly difficult to target with existing methods, highlighting T. gondii's potential as a tool for delivering intracellular proteins to neurons.