Nanoparticles supply microRNAs to muscle stem cells for potential muscular dystrophy treatment

In international collaboration, researchers have made important breakthroughs in the therapeutic delivery of microRNAs against the previously untreated disease, Duchenne muscular dystrophy.

Duchenne muscular dystrophy is a hereditary disorder characterized by progressive loss of muscle mass due to mutations in the dystrophin gene. Without the corresponding functional protein, muscles will not function properly or repair, resulting in degradation of the skeletal, heart and lung muscles. The dystrophin gene is located on the X chromosome, which affects men mostly, but women are usually carriers.

Researchers have developed a strategy to treat muscle dystrophy, which uses nanoparticles as vehicles to transport therapeutic microRNAs to muscle stem cells. Once inside muscle stem cells, the nanoparticles release microRNAs and stimulate muscle fiber production.

This study has been published in the journal Nature Communications.

MicroRNAs are a class of RNA molecules that play an important role in gene regulation. Delivery of microRNAs through the bloodstream is complicated due to their low stability and penetration. In this context, nanoparticles act as safe biocarriers and improve delivery of this therapy.

In their study, researchers developed aptamers, molecules that selectively recognize certain other molecules, in this case proteins found in muscle stem cells. By combining aptamers with nanoparticles, we were able to release microRNAs in muscle stem cells with extremely accurate accuracy and re-activate muscle regeneration.

Researchers have reported system activity in cell and animal models, observing recovery at the functional level as well as muscle regeneration at the cellular level. The muscles in treated mice improved, became stronger after treatment, and the functional capacity of the mice improved.

Therapeutic molecule collided with the target

Generally, when nanoparticles are administered intravenously, they usually accumulate in the liver or kidneys. Furthermore, in this process, the nanostructures are coated with proteins from the plasma. This is the so-called protein corona that regulates the biodistribution of nanoparticles. These processes significantly affect where nanoparticles accumulate, reducing the effectiveness of the treatment.

In this study, nanovehicles modified with the aptamers preferentially accumulate in muscles, particularly muscle stem cells, where they release microRNAs that activate muscle regeneration.

Development of aptamers

An aptamer is a DNA or RNA strand that employs a specific three-dimensional structure and is capable of binding to a target molecule with high affinity. Those surgeries are similar to antibodies surgeries, and as biosensors, they offer a wide range of possibilities in treatment and diagnosis.

Looking for an aptamer that matches your desired therapeutic target is like looking for a needle in a haystack. To do this, a repetitive process called SELEX (systematic evolution of ligands by exponential enrichment) is often used to promote the selection of DNA or RNA sequences with high affinity for the target molecule. To do this, a random library of trillions of nucleic acid sequences is generated and incubated with the target molecule. Some of the strands in the library may have affinity for the target molecule.

A family of highly affinity sequences is then selected through subsequent washing and amplification steps. Finally, the most efficient sequences are usually optimized for stability and functionality of therapeutic or diagnostic applications.

In their recent study, researchers conjugated nanoparticles with aptamers to α7/β1 integrin. It is a highly specific surface receptor expressed by differentiated muscle fibers that are virtually absent in muscle progenitor cells and other organs and tissues. In this way, aptamer-bound nanoparticles were able to efficiently target muscles, with high selectivity towards muscle stem cells.

Alvaro Somoza, the lead author of the study, is extremely enthusiastic about the results. “There are two very noteworthy things to point out. First, effective delivery of microRNAs to the desired organ increases the effectiveness of treatment. Meanwhile, this approach is the brain, kidneys and liver. Prevents the accumulation of other organs such as. This is the key to preventing side effects.”

Nucleic acid delivery platforms such as microRNAs developed by Professor Somoza’s team are biocompatible, non-toxic, non-immunogenic and easy to release different types of oligonucleotides for the treatment of a variety of diseases. It can be adapted. .

This work is a collaboration between researchers at Imdea Nanociencia (Madrid), led by Alvaro Somoza. del Sacole (Rome), the University of Catricia, led by Daniela Palacios. and the University of Bordeaux, led by Jean Jacques Tourmet.