Mitochondria, the powerhouse of the cell, are critical in regulating cellular functions such as growth, survival, and energy production. Due to their central role in cancer cell metabolism, these organelles have become key targets for innovative cancer therapies. Mitochondrial genetics and metabolism contribute significantly to cancer progression, influencing processes like cell motility, invasion, and the tumor microenvironment. Despite these promising insights, the development of therapies targeting mitochondria has faced significant hurdles.
Current mitochondrial-targeted treatments, such as mitocans and mitochondriotoxics, focus on disrupting key signaling pathways and proteins involved in cellular energy processes, including hexokinase and Bcl2 family proteins. However, the presence of mutations in cancer cells limits the long-term effectiveness of these therapies, making it difficult to achieve sustained clinical success. A promising advancement in the field is mitochondrial optogenetics (mOpto), a technique that introduces light-gated channelrhodopsins into mitochondria, enabling controlled depolarization of the mitochondrial membrane potential (∆Ψm) and subsequent cell death. While this technology showed promise, its reliance on external light sources restricts its application to surface-level tumors.
To overcome this limitation, researchers have developed mitochondrial luminoptogenetics (mLumiOpto), an innovative approach that utilizes an internal light source. This technique combines cationic channelrhodopsin (CoChR), a protein activated by blue light, with nanoluciferase (NLuc), a bioluminescent enzyme. The genes encoding these molecules are selectively expressed in cancer cells using a cancer-enhanced promoter. Upon delivery to cancer cells, NLuc generates light that activates CoChR, triggering mitochondrial collapse and ultimately leading to cell death.
The delivery of this gene therapy is facilitated by a modified adeno-associated virus (AAV) coupled with a monoclonal antibody. This delivery system ensures that the therapy targets cancer cells specifically while sparing healthy tissue. The virus is encapsulated in nanocarriers derived from human cells, enhancing its stability and effectiveness. The monoclonal antibody further enhances specificity by binding to receptors on the surface of cancer cells.
The therapeutic potential of mLumiOpto was tested in preclinical mouse models of glioblastoma and triple-negative breast cancer, both of which are notoriously difficult to treat. The results were encouraging. In glioblastoma models, mLumiOpto significantly reduced tumor size and extended survival. Imaging studies confirmed that the effects were confined to cancerous tissues, with no observable damage to healthy cells. “We disrupt the membrane so mitochondria cannot function, either in energy production or signaling, leading to programmed cell death followed by DNA damage. Both mechanisms contribute to killing the cancer cells,” explained Lufang Zhou, co-lead author and professor at The Ohio State University.
Zhou’s research team worked closely with X. Margaret Liu, a chemical engineering professor specializing in nanoparticle-based therapies, to refine the AAV delivery system for improved stability and cancer specificity. Liu’s expertise in creating targeted anti-cancer therapies was key in designing the delivery particles, which resemble naturally occurring extracellular vesicles in human blood. “This design ensures stability in the human body because the particles are derived from human cell lines,” Liu noted.
In addition to its direct tumor-killing effects, mLumiOpto appears to stimulate the immune system, further enhancing its therapeutic potential. The monoclonal antibody component triggers an immune response within the tumor microenvironment, potentially boosting the therapy’s effectiveness. This combination of targeted cell death and immune activation could be particularly valuable for treating cancers that are resistant to conventional therapies.
“Our approach targets mitochondria directly, using external genes to activate a process that induces cell death,” Zhou explained. “This is a distinct advantage, and our studies show it is effective in killing various types of cancer cells.” The team had previously demonstrated that disrupting the electrical charge of the mitochondrial inner membrane (IMM) could be achieved using light-activated proteins. The mLumiOpto system takes this concept further by creating light within the cells themselves, making the therapy more feasible for clinical application.
The success of mLumiOpto has been demonstrated across multiple cancer types. In triple-negative breast cancer models, the therapy reduced tumor burden and improved survival. The technology’s versatility and precision offer promising potential for broader clinical applications.
Ohio State University has filed a provisional patent for the mLumiOpto technology, and researchers are continuing to explore its use in other cancers while refining the delivery mechanisms. This breakthrough represents a significant step forward in the development of targeted, minimally invasive cancer treatments, offering hope for more effective therapies in the ongoing fight against cancer.
By Impact Lab
