Researchers are advancing a groundbreaking approach to cancer treatment by targeting the energy centers of cancer cells—mitochondria—with precision, causing significant damage to these vital structures and triggering widespread cell death. In a new study, scientists combined cutting-edge gene therapy techniques with nanoparticles engineered to selectively target cancer cells. The experiments demonstrated remarkable success, showing the ability of this therapy to shrink aggressive glioblastoma brain tumors and triple-negative breast cancer tumors in animal models.
Mitochondria are the primary energy producers within cells, essential for their survival and functioning. They also serve as critical signaling hubs. For years, scientists have viewed these energy centers as potential targets for cancer therapies, but the challenge lies in the impermeable inner membrane of mitochondria. This structure makes it difficult to deliver therapeutic agents that could effectively disrupt their functions. However, researchers have now devised a solution with a novel technology named mLumiOpto, which utilizes light-activated electrical currents to disrupt mitochondria and trigger programmed cell death.
According to Lufang Zhou, professor of biomedical engineering and surgery at The Ohio State University and co-lead author of the study, the new technology achieves its goal by design. “We disrupt the membrane, so mitochondria cannot work functionally to produce energy or work as a signaling hub. This causes programmed cell death followed by DNA damage—our investigations showed these two mechanisms are involved and kill the cancer cells,” Zhou explained. He collaborated with X. Margaret Liu, professor of chemical and biomolecular engineering at Ohio State, who developed the targeted nanoparticles used to deliver the gene therapy exclusively to cancer cells. Both Zhou and Liu are also affiliated with The Ohio State University Comprehensive Cancer Center.
This innovative research has been published in the December issue of the journal Cancer Research.
Cracking the Mitochondrial Code
Zhou’s lab has been exploring ways to exploit the vulnerabilities of mitochondria for years. About five years ago, his team discovered that the electrical charge differential across the mitochondrial inner membrane, which is crucial for its stability and function, could be exploited to induce its breakdown. This breakthrough paved the way for the development of mLumiOpto. The team leveraged this principle to develop a method for delivering light-activated gene therapy directly to cancer cells, bypassing traditional pharmaceutical approaches that target specific cancer cell pathways.
“Previous attempts to use a pharmaceutical reagent against mitochondria targeted specific pathways of activity in cancer cells,” Zhou said. “Our approach targets mitochondria directly, using external genes to activate a process that kills cells. That’s an advantage, and we’ve shown we can get a very good result in killing different types of cancer cells.”
The researchers initially demonstrated that the mitochondrial inner membrane could be disrupted by a protein that generates electrical currents. This protein could be activated by external laser light. In their latest work, however, the team went a step further by engineering an internal light source to make the technology more practical for clinical applications.
How mLumiOpto Works
The strategy involves introducing genetic information for two types of molecules into cancer cells. The first molecule is a light-sensitive protein known as CoChR, which can generate positively charged electrical currents. The second is a bioluminescent enzyme that emits light. These molecules are delivered using a specially designed viral vector derived from the adeno-associated virus (AAV), a commonly used gene therapy tool. Once inside the cancer cells, the genes for these molecules are expressed in the mitochondria.
A follow-up injection of a chemical activates the bioluminescent enzyme, which then emits light to trigger the CoChR protein. This, in turn, disrupts the mitochondrial membrane, causing the organelles to collapse. The resulting loss of energy production and signaling triggers programmed cell death and DNA damage, effectively killing the cancer cells.
Ensuring Cancer-Specific Targeting
One of the biggest challenges in cancer therapy is avoiding harm to normal cells. The research team addressed this issue by enhancing the specificity of their delivery system. Liu’s lab specializes in designing anti-cancer therapies that precisely target tumor cells. For this project, the researchers modified the AAV viral vector with a cancer-specific promoter protein, ensuring that the therapeutic genes are only expressed in cancer cells.
To further improve the precision and stability of the therapy, the team manufactured the AAV particles in human cells. This process encased the viral vectors in natural nanocarriers resembling extracellular vesicles, which circulate naturally in the human bloodstream. These nanocarriers make the gene therapy more stable and reduce the risk of triggering an immune response in the body.
Additionally, the researchers attached a monoclonal antibody to the delivery system. This antibody is designed to recognize and bind to specific receptors on the surface of cancer cells, ensuring that the therapeutic particles are directed exclusively to the tumor. “This monoclonal antibody can identify a specific receptor, so it finds cancer cells and delivers our therapeutic genes. We used multiple tools to confirm this effect,” Liu said.
Promising Results in Preclinical Models
The therapy was tested in mouse models of glioblastoma and triple-negative breast cancer, two highly aggressive and difficult-to-treat cancers. The results were promising: the treatment significantly reduced tumor size compared to untreated animals. Moreover, in glioblastoma models, the therapy not only shrank tumors but also extended the survival of the mice.
Imaging studies confirmed that the effects of the gene therapy were confined to cancer tissues, with no detectable impact on normal tissues. Furthermore, the attachment of the monoclonal antibody appeared to enhance the therapy’s efficacy by inducing an immune response in the tumor microenvironment. This immune activation could provide additional benefits by helping the body’s natural defenses fight the cancer.
Future Directions
The researchers are now investigating the broader potential of the mLumiOpto technology for treating other types of cancer. They are also exploring additional therapeutic effects, such as the potential to use the immune response induced by the therapy to enhance its effectiveness further. A provisional patent application for the technology has been submitted by Ohio State University.
This work represents a significant step forward in the development of targeted cancer therapies. By combining advanced gene therapy with precise delivery mechanisms and innovative use of bioluminescence, the researchers have created a powerful tool for combating some of the most challenging cancers. If successfully translated to clinical settings, mLumiOpto could revolutionize cancer treatment and offer new hope to patients with aggressive and treatment-resistant tumors.
Source: The Ohio State University