Distribution and Localization of Specifically Modified Exosomes Can Improve the Treatment of Muscular Dystrophies

Carrier of Therapeutic Information

Exosomes are the smallest subtype of extracellular vesicles. They range in size from 30 to 100 nm, which allows them to more easily pass between individual cells. They are composed of a cell membrane and various proteins with informational molecules, such as coding mRNA or signaling microRNA. Thanks to this, they can significantly influence and regulate processes in recipient cells. For this reason, they are considered a promising means of carrying information and influencing immune responses in their environment.

Advances in research on the structure and properties of exosomes have allowed scientists to find ways to modify exosomes to carry specific therapeutic cargo while targeting specific cells and tissues. The research team from the Institute of Pathophysiology and Transplantation at the University of Milan decided to utilize this for the repair and regeneration of damaged tissues in various forms of muscular dystrophy. To achieve this, the scientists enriched exosomes with the protein annexin A1 (AnxA1).

AnxA1 is a mediator in a number of important immune responses, as it can reprogram macrophages from a generally pro-inflammatory state to an anti-inflammatory state. AnxA1 therefore plays a significant role in anti-inflammatory and reparative processes and the activation of apoptosis in neutrophils.

The effect of exosomes loaded with AnxA1 was studied on satellite muscle cells taken from the hind limbs of mice specifically bred for Duchenne muscular dystrophy research. The research team found that macrophages treated with the protein AnxA1 showed increased production of anti-inflammatory genes, unlike untreated macrophages. Repeated administration of AnxA1 gradually led to the suppression of the dystrophic inflammatory environment.

Targeting Exosomes to Specific Locations

However, the question was how to deliver such modified exosomes to the damaged muscle cells. The systemic biodistribution and targeting of exosomes to a specific site in vivo is considerably complicated. Lipids and proteins contained in exosomes have a significant impact on their pharmacokinetics.

In further experiments on mouse cells, the scientists tested how exosomes behave within the body. They discovered that after systemic injection, the protein AnxA1 accumulates in the filtering organs of mice – the liver and spleen. In contrast, after direct application to dystrophic muscle cells, the necessary processes were actively triggered. After a week of administration, muscle mass restoration was also observed in mice.

The researchers then focused on creating a carrier capable of delivering exosomes to the targeted location directly in the patient’s body. They designed a system of ferromagnetic nanotubes (NT-MAG), on whose surface the modified exosomes are attached. The nanotubes are first applied to the body via a systemic injection and subsequently targeted to the specific site using an external magnetic field.

The use of exosomes as carriers of the AnxA1 protein and the concurrent use of magnetically guided nanocarriers thus, according to the authors of the research, opens the way to an accessible and effective method that could significantly improve the quality of life for patients with muscular dystrophy.

Editorial Team, Medscope.pro

Source: Villa C., Secchi V., Macchi M. et al. Magnetic-field-driven targeting of exosomes modulates immune and metabolic changes in dystrophic muscle. Nat Nanotechnol 2024 Oct; 19 (10): 1532–1543, doi: 10.1038/s41565-024-01725-y.