Researchers have achieved a significant breakthrough in cancer treatment by harnessing the potent capabilities of the body’s natural killer (NK) cells. These innovative nanodrones are designed to selectively target tumors, allowing NK cells to suppress cancer growth effectively. This discovery paves the way for the development of tumor-specific immunotherapies, particularly for challenging-to-treat cancers.

NK cells are specialized white blood cells known for their ability to destroy infected and diseased cells, including cancer cells, without prior exposure to a specific pathogen. Researchers from the Ulsan National Institute of Science and Technology (UNIST) in South Korea have unlocked the potential of NK cells by creating nanodrones that engage these cells and direct them to target and eliminate cancer cells.

NK cells combat cancer by releasing cytotoxic (cell-killing) granules and cytokines that not only directly destroy cancer cells but also recruit other immune cells to the tumor site, enhancing the immune response against cancer. NK cell-based immunotherapies have been under study for a decade, with a focus on using NK cell engagers—engineered proteins that selectively bind to both NK cells and target cancer cells, bringing them into close proximity for effective cancer cell destruction.

In their recent study, the researchers developed a nanoscale “protein cage” derived from the bacterium Aquifex aeolicus (AaLS) to serve as a platform for the targeted delivery of NK cell-engaging nanodrones (NKeNDs). These nanodrones activate NK cells and transport them to specific cancer cells for eradication. To ensure precise delivery, the researchers attached CD16-targeting nanobodies and cancer cell-specific ligands, HER2 and EGFR affibodies, to the nanodrones’ surface.

The CD16 receptor on NK cells enhances their antibody-dependent cellular cytotoxicity. HER2 (human epidermal growth factor 2) and EGFR (epidermal growth factor receptor) are proteins associated with cancer cell growth.

Testing their NKeNDs on HER2-overexpressing ovarian cancer cells and EGFR-overexpressing breast cancer cells, the researchers observed that the nanodrones bound to their respective target cancer cells and activated human NK cells. The extent of NK cell-mediated cytotoxicity against cancer cells depended on both the number of NK cells and the concentrations of HER2 and EGFR NKeNDs.

Crucially, non-targeted cells remained unaffected by NK cell-mediated cytotoxicity, regardless of the number of NK cells applied. This indicates that NKeNDs primarily mediate NK cell toxicity through direct interaction with target cancer cells.

In animal experiments using tumor-bearing mice, the researchers administered HER2@NKeND along with human peripheral blood mononuclear cells (PBMCs), which contain NK cells. The combination effectively suppressed tumor growth, while administering HER2@NKeND alone had no significant impact. Histological analysis revealed specific cell death within the target tumors without damage to major organs. The tumors also exhibited significant infiltration of NK cells.

When NK cells were extracted from PBMCs and injected along with HER2@NKeND, tumor growth suppression and increased infiltration of human leukocytes and NK cells were observed. However, the tumor-suppressing ability was slightly lower than when using whole human PBMCs. The researchers attributed this to the absence of other immune cells, such as T cells, and supporting substances that enhance NK cells’ cytotoxic activity.

The researchers believe that their cancer-targeting NKeNDs hold great potential as protein-based cancer immunotherapeutics for selectively treating target tumors. They suggest that this strategy could be extended to treat various cancer types by simply altering the cancer-targeting and immune cell-recruiting ligands, offering new possibilities for the advancement of recombinant NK cell engagers.

By Impact Lab