'Smart' Nanoparticles Could Deliver mRNA Cancer Therapy Directly to Tumors
Australian researchers have developed nanoparticles that precisely deliver mRNA therapy to immune cells inside tumors, reprogramming them to fight cancer again. Tests in mice showed slowed tumor growth with no detected harm to other organs.
A research team at the University of Adelaide, led by professor Chunxia Zhao, has developed a new approach to overcoming one of the biggest obstacles in cancer immunotherapy: the ability of tumors to disable the very immune cells meant to fight them. The study was published this week in the journal Science Advances.
The target of the therapy is tumor-associated macrophages — immune cells that cancer reprograms to block the arrival and activity of T cells, one of the body's principal weapons against tumors. The researchers used an mRNA therapy carrying instructions to produce CXCL9, a chemical signal that recruits T cells.
Precision delivery
To ensure the mRNA reached only the tumor site, rather than risking an overactive immune response elsewhere in the body, the team designed what they call "smart" nanoparticles. As in standard mRNA therapies, the molecule is encased in a fatty lipid envelope, but here it was also studded with antibodies that bind to TREM2, a protein found on the surface of immunosuppressive tumor-associated macrophages. This allows the treatment to reach only the specific cells that need reprogramming. The nanoparticles also carried a drug called resiquimod, which stimulates certain immune pathways.
In laboratory tests, previously suppressed macrophages began producing CXCL9 along with other markers of an active immune state — expression of the protein NOS2 increased 89.5-fold — while markers of immunosuppression notably decreased.
Results in mice
After three doses in mice with aggressive breast cancer, tumor growth slowed. CXCL9 concentration was roughly four times higher than in the control group, and T-cell activity was detected. The proportion of macrophages showing immunosuppressive characteristics dropped by 63 percent.
When combined with existing immune checkpoint inhibitor therapies, the treatment did not further shrink tumors, but it did produce notable immune system changes, including increased numbers of various T-cell types within tumors and nearby lymph nodes — a sign associated with a potentially more durable immune response. No negative effects on other organs were detected.
The researchers describe the findings as an important proof of concept, but caution that significant further safety research is needed before the approach could move toward human clinical trials.
