Illustration shows depicts treating lung tumors with lipid nanoparticles loaded with follistatin.
Image Credit: Parinaz Ghanbari
Scientific Frontline: Extended "At a Glance" Summary: Dual-Targeted mRNA Therapy for Lung Cancer and Cachexia
The Core Concept: This novel therapeutic approach utilizes specialized lipid nanoparticles (LNPs) to deliver follistatin messenger RNA (mRNA) directly to lung tumors, simultaneously inhibiting cancer growth and reversing cachexia, a severe muscle-wasting syndrome.
Key Distinction/Mechanism: Unlike conventional LNPs, which typically accumulate in the liver following systemic administration, these modified LNPs bind to the blood serum protein vitronectin. The vitronectin directs the LNPs specifically to lung cancer tumors by interacting with integrin receptors that are overexpressed on the tumor surface. Once absorbed, the mRNA instructs the cells to produce follistatin, a protein known to suppress tumor progression and stimulate muscle tissue growth.
Major Frameworks/Components:
- Lipid Nanoparticles (LNPs): Nanoscale delivery vehicles composed of fatty acids designed to carry genetic material intravenously without degrading.
- Follistatin mRNA: The therapeutic genetic payload that triggers the endogenous production of the dual-action follistatin protein.
- Vitronectin: A naturally occurring blood serum protein that binds to the LNPs and acts as a homing beacon.
- Integrin Receptors: Surface receptors overexpressed on lung cancer cells that interact with vitronectin to facilitate the precise cellular uptake of the LNPs.
Branch of Science: Oncology, Pharmacology, Nanomedicine, and Molecular Genetics.
Future Application: While currently proven in a mouse model, future applications include advancing the treatment to human clinical trials. This LNP-vitronectin targeting mechanism also provides a promising foundational platform for the systemic delivery of other mRNA therapeutics directly to lung tumors.
Why It Matters: Lung cancer is the leading cause of cancer death in the United States, and cachexia is responsible for up to 30% of those fatalities by causing irreversible muscle and weight loss. This therapy achieved a 2.5-fold greater reduction in tumor burden compared to conventional LNPs, offering a highly efficient, dual-action treatment that fights the primary cancer while simultaneously combating its most debilitating secondary syndrome, entirely without adverse effects observed in preclinical trials.
Researchers at Oregon State University have developed a technique for simultaneously treating lung cancer and a serious muscle-wasting condition that often accompanies it.
The study, published in the Journal of Controlled Release, involves lipid nanoparticles delivering therapeutic genetic material to lung tumors.
In a mouse model, scientists led by Oleh Taraula and Yoon Tae Goo of the OSU College of Pharmacy showed that a type of nanocarrier loaded with follistatin messenger RNA is able to accumulate in tumors. Once there, the mRNA triggers cells to produce the follistatin protein, which plays a key role both in inhibiting tumors and promoting muscle tissue growth.
The lipid nanoparticles, or LNPs, can be administered intravenously and reach the lungs courtesy of another protein, vitronectin, that’s found in blood serum. Lipids are fatty acids and similar organic compounds including many natural oils and waxes. Nanoparticles are tiny pieces of material ranging in size from one- to 100-billionths of a meter.
“We found that these LNPs bind vitronectin in the bloodstream, which then directs them to lung cancer tumors by interacting with integrin receptors that are overexpressed on the tumor surface,” Taratula said.
Integrin receptors are like bridges and that regulate how cells respond to their surrounding environment.
“Systemic delivery of mRNA therapeutics to lung cancer tumors has been a significant challenge in our field, and this work offers a promising solution,” Taratula said. “Compared to conventional LNPs, which tend to accumulate in the liver upon systemic administration, our approach achieved an approximately 2.5-fold greater reduction in tumor burden.”
Lung cancer is the third most common cancer in the United States and the leading cause of cancer death (skin cancer is the most common, followed by prostate cancer for men and breast cancer for women).
The American Cancer Society estimates the U.S. will see about 230,000 new lung cancer cases this year and about 125,000 lung cancer deaths. Overall, about 5% of people will develop lung cancer; the risk is higher among smokers.
Often accompanying lung cancer is a debilitating muscle-wasting syndrome known as cachexia, which kills as many as 30% of the cancer patients it afflicts. People with cachexia will lose weight even if they eat, and not just fat but muscle mass as well.
“By loading our LNPs with follistatin mRNA, we developed a therapy that simultaneously targets lung cancer and cancer cachexia, all without adverse effects,” Taratula said. “More preclinical work is necessary, but we’re very encouraged by what we’ve seen so far and hope that testing in humans is down the road.”
The College of Pharmacy’s Vladislav Grigoriev, Tetiana Korzun, Ammar Salem, Kongbrailatpam Shitaljit Sharma, Prem Singh, Chrissa Kioussi and Olena Taratula also contributed to the research, as did Daniel Marks of Endevica Bio, a company that develops peptide therapies.
Funding: Supporting the study were the National Cancer Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Research Foundation of Korea.
Published in journal: Journal of Controlled Release
Title: Endogenous targeting lipid nanoparticles for systemic mRNA delivery to lung cancer tumors
Authors: Yoon Tae Goo, Vladislav Grigoriev, Tetiana Korzun, Ammar Salem, Kongbrailatpam Shitaljit Sharma, Prem Singh, Chrissa Kioussi, Olena R. Taratula, Daniel L. Marks, and Oleh Taratula
Source/Credit: Oregon State University | Steve Lundeberg
Reference Number: ongy040626_01