Crazy Discovery: Tiny Nanocarriers Found in Mice Naturally Heal Inflammation and Tissue Damage!

The researchers conducted experiments in cell cultures and mice to demonstrate the therapeutic potential of these nanoparticles, which are extracellular vesicles similar to those circulating in the human bloodstream and in biological fluids that carry messages between cells.

The hope is that a drop of solution containing these nanocarriers, delivered to the lungs through the nose, could treat acute respiratory distress syndrome (ARDS), one of the most common causes of respiratory failure that leads to putting patients on a ventilator. In ARDS, out-of-control inflammation in the lungs so severely overloads the immune system that immune cells cannot deal with the initial cause of the damage.

“These extracellular vesicles would be an alternative therapy for ARDS that gives your own immune system a fighting chance,” said lead author Natalia Higuita-Castro, an associate professor of biomedical engineering and neurosurgery at The Ohio State University. “The problem with ARDS is that there’s a shift in the normal balance that favors inflammation. By introducing anti-inflammatory agents, you shift that balance to a more level stage so that the immune system can resolve the underlying problem.”

The study was recently published online in the journal advanced materials.

Beginning the engineering process with adult skin cells called dermal fibroblasts is a major secret to the success of this technology, said Higuita-Castro, also director of advanced therapy and engineering at the Davis Heart and Lung Research Institute in the Faculty of Medicine.

Many nanocarriers are engineered from stem or progenitor cells that can differentiate into other cell types, but also have mysterious properties that are not yet fully understood.

“The use of skin cells from adult animals is very important to us because we wanted to demonstrate the feasibility of translating this into clinical settings, where we could have a universal donor cell from adult patients,” Higuita-Castro said. “Dermal fibroblasts are readily available, we can culture them, they are used clinically for grafting and wound healing, and they don’t produce an immune response like you see with other cell sources.”

To create the vesicles, scientists apply an electrical charge to a donor skin cell to temporarily open holes in its membrane and deliver externally obtained DNA inside. The donor cell converts that genetic information into one of two anti-inflammatory proteins, as well as messenger RNA, molecules that translate the instructions for making more of these functional proteins.

Those materials are the payload inside these nanocarriers, the surfaces of which are tagged with a molecule that allows interaction with specific cells to improve their retention in the lungs. In this study, separate nanocarriers were packaged with one of two anti-inflammatory proteins, IL-4 or IL-10, plus mRNA for recipient cells in the lung to process and produce more protein.

“The proteins have an immediate effect, and the addition of mRNA will give a more sustained effect,” said Higuita-Castro, also a senior faculty member at the Ohio State Institute for Gene Therapy.

The different proteins were not combined in one vesicle for a reason: “Our vision for clinical applications is to have a mix-and-match platform based on the needs of the patient,” he said. “That way, we could also administer lower doses multiple times, if needed, and re-dosing with these nanocarriers will be fine because they don’t trigger a significant immune response.”

Cell culture experiments suggested that these vesicles could be used as a pretreatment in diseased patients at high risk of developing ARDS. Studies in mice showed its potential to help patients who are already severely ill.

After injecting the mice with a molecule that triggered major inflammation in the lung, the researchers gave them a single drop of liquid loaded with engineered nanocarriers that traveled directly to their injured lungs and went to work. Inflammation was reduced as expected, but repeated experiments on the animals showed that the vesicles also reduced damage to lung tissue.

Even more exciting for Higuita-Castro was the finding that cells in the treated lungs secreted substances with additional therapeutic benefits, including antioxidants and more anti-inflammatory molecules.

“Honestly, that was mind blowing,” he said. “It’s a local treatment because it’s delivered intranasally and it stays in the lung because we designed it that way, but it has a global effect that’s really powerful.”

Finding a safe and effective treatment for ARDS is an important medical need. The current use of ventilators and steroids has many side effects, and while the dangerous lung condition used to be relatively rare, the number of cases has skyrocketed during the COVID-19 pandemic.

“COVID-19 shed light on the lack of effective therapeutic options for acute lung injury in general,” Higuita-Castro said.

There’s more to do with nanocarriers, including pinning down the fine details of everything they can do to repair damaged lungs and testing the therapy in larger animals. But Higuita-Castro is optimistic about the future of technology.

“These extracellular vesicles are naturally occurring nanoparticles and we think they’re great because nature is the best example we could have, having had millions of years to optimize the system,” he said.

This research was supported by seed funding from the Ohio State Office of COVID-19 Research and grants from the National Institutes of Health.

The work was directed by the co-authors Ana Salazar-Puerta and María Rincon-Benavides. Other Ohio State co-authors included Tatiana Cuellar-Gaviria, Julian Aldana, Lilibeth Ortega-Pineda, Devleena Das, Daniel Dodd, Charles Spencer, Binbin Deng, David McComb, Joshua Englert, Samir Ghadiali, Loren Wold, and Daniel Gallego-Perez. Gabriela Vasquez Martinez and Diana Zepeda-Orozco of Nationwide Children’s Hospital also worked on the study.