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Lung cancer is one of the most common cancers and has one of the lowest survival rates in the world. Cytokines, which are small signaling proteins, such as interleukin-12 (IL-12), have shown considerable potential as potent tumor suppressors. However, their applications are limited due to many severe side effects.

In a paper published on January 11 Nature Nanotechnology, Biomedical engineering professor Ki Cheng and his research group show that the use of nanobubbles, called exosomes, through an inhalation therapy method can directly deliver IL-12 messenger RNA (mRNA) to the lungs. . mRNAs are the blueprints for producing specific proteins that participate in a variety of cellular functions. While scientists have previously used liposomes (small fat-based particles) or lipid nanoparticles (LNPs) to deliver mRNA, this method has several problems, including a lack of tissue homing, where the particles cannot target the target. Do not go to the limb, and concerns about it. Potential toxicity after long-term exposure. Over the past 15 years, Cheng’s group has been developing exosomes for use as better drug delivery carriers than liposomes and LNPs in specific indications.

New method

Until now, clinicians have only been able to use IL-12 to treat cancer by injecting it directly into the tumor or into the bloodstream. Cheng’s laboratory found that by inhaling IL-12 mRNA in exosomes to patients—in this case, mice—not only could locally concentrated IL-12 be delivered to the lungs, but cancer cells with minimal side effects. Can fight better. The inhalation method is more efficient at producing high concentrations of IL-12 where it is needed than using other methods of mRNA delivery such as liposomes.

“Exosomes are usually injected systemically into the bloodstream,” Cheng said. “In this new study, we show that inhaled exogenous substances can efficiently reach the lung and deliver the lung cancer-preventing cargo, IL-12 mRNA. “This is a major step forward in advancing the development of new inhaled drugs to treat cancer, which has one of the lowest five-year survival rates in the world.”

Transforming immune cells into powerful defenders

Inhaling nanobubbles with an IL-12 blueprint can kick-start the lung’s immune cells, turning them into powerful defenders equipped to release substances that directly target tumor cells. And destroy. In addition, IL-12 helps train these immune cells to “remember” the unique characteristics of tumor cells. As a result, if the tumor tries to invade again, these well-informed immune cells are ready to quickly recognize and eliminate the tumor. Additionally, these supercharged immune cells can spread their new knowledge to other, untrained immune cells throughout the body, creating an army of defenders. This means that even if tumor cells try to spread beyond their original site, like the lungs, these evolved immune cells can see them and kill them, creating a whole-body defense against cancer. System offers. as well as increased tumor resistance to re-challenges.

Combining utility with simplicity

The researchers say this strategy stands out as a potent IL-12 mRNA delivery system in the lung microenvironment, and combines simplicity with efficacy against primary tumors and metastases. Compared to other nanoparticle controls, exosomes promoted IL-12 expression with reduced toxicity. And patients are likely to be happier simply inhaling the treatment rather than receiving an intratumoral injection.

Next Steps

Cheng’s group is now working with ophthalmologists at Columbia University Irving Medical Center to translate their findings into the clinic to benefit lung cancer patients.

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