KAIST develops nanoparticle platform combining immuno-oncology and gene therapy

South Korean researchers have developed a new anticancer platform that tricks tumor cells into broadcasting their own location to the immune system while simultaneously delivering gene therapy agents.

KAIST announced Tuesday that a research team led by Kim Yu-cheon, a professor in the Department of Biological and Chemical Engineering, has developed a "helical polypeptide nanoparticle" platform capable of inducing immunogenic cell death in cancer cells and delivering a range of gene therapy agents directly into those cells.

Immunogenic cell death is a process in which dying cancer cells release danger signals that alert surrounding immune cells and trigger an attack. Polypeptides are polymer compounds made up of long chains of amino acids.

Research into using nanoparticles to deliver drugs and genetic material to cancer cells and activate immune responses has grown rapidly in recent years. It has remained unclear, however, which properties of nanomaterials induce cellular stress and activate anticancer immune responses.

After comparing and analyzing a range of nanoparticles, the team found that not only the composition of the nanomaterial but also its helical shape is a key factor determining therapeutic efficacy.

The helical nanoparticles preferentially seek out and penetrate cancer cells, which have different electrical membrane properties than normal cells. Once inside, they disrupt the membranes of mitochondria and other organelles, inflicting severe stress on the cancer cell.

As the stressed cancer cells die, they release damage-associated molecular patterns — distress signals that effectively announce the presence of a dangerous cell to the surrounding environment. Immune cells that detect these signals then recognize the previously hidden cancer cells as threats and begin attacking them. In other words, the platform forces cancer cells to reveal their own location to the immune system.

The nanoparticles also serve as carriers for gene therapy agents, going beyond simply triggering an immune response. While messenger RNA (mRNA) and small interfering RNA (siRNA) are typically difficult to deliver into cells, the team's nanoparticles transported them effectively all the way to the cytoplasm.

In mouse models of melanoma and colorectal cancer, the team loaded the helical nanoparticles with siRNA targeting PD-L1, an immune-evasion protein, and administered them to the animals. Tumor growth was suppressed by approximately 70–80 percent. A significant increase in cytotoxic T cells — which directly attack cancer cells — infiltrating the tumor was also observed, indicating a substantially enhanced anticancer immune response.

The most immediate application of the technology lies in developing next-generation anticancer immunotherapy drugs based on non-viral gene delivery systems. The platform can deliver CRISPR/Cas9 gene-editing tools or immune-activating mRNA therapeutics directly into tumor tissue at high efficiency, blocking the mechanisms by which cancer cells resist treatment at the source.

"This research establishes a new physicochemical design principle showing that the morphological secondary structure of synthetic nanomaterials can stimulate intracellular organelles and govern biological immune responses," Kim said. "It can be broadly applied as a replacement for protein viral vectors in next-generation vaccine formulation design, genomic stability research, and nanomedicine platforms for treating a wide range of intractable tumors."

The findings were published May 28 in Biomaterials, an international journal in the field of biomaterials.