Scientists at Nanyang Technological University, Singapore have created microscopic peptide droplets that shrink hard-to-treat colorectal tumors by roughly 67 per cent in mice by delivering gene-silencing molecules into cancer and immune cells. The patent-pending system uses small interfering RNA, or siRNA, to block production of two proteins that help cancer cells hide from immune attack. In animal tests, the combined siRNA treatment suppressed tumor expansion to a level matching a combination of anti-PD-1 and anti-PD-L1 antibody treatments used as a comparison benchmark.
The researchers deliberately tested their approach against microsatellite-stable colorectal cancer, or MSS colorectal cancer, which represents roughly 85 per cent of colorectal cancers but responds poorly to immune checkpoint inhibitors that have revolutionized treatment for other cancers. Laboratory experiments showed the treatment increased T-cell activation and immune signalling and helped the T cells destroy more colorectal cancer cells. The team used two separate peptide microdroplet formulations together as a combination therapy: one formulation, siPD-1@THC, carried siRNA against PD-1 and was fitted with anti-CD3 antibodies to help the droplets enter T cells, while the second, siPD-L1@HC, carried siRNA against PD-L1 into colorectal cancer cells. More than 1.9 million people were diagnosed with colorectal cancer in 2022, and the disease causes over 900,000 deaths annually, making it the second leading cause of cancer death worldwide.
Professor Ali Miserez, senior author of the study published in the peer-reviewed journal Biomaterials, explained the approach works from inside both types of cells. "The siRNA destroys the instructions they need to make these proteins," he said. "What is important about our microdroplets is that they can carry large amounts of siRNA into the cells where it needs to act." The researchers estimate that an siRNA-based approach could potentially cost five to 10 times less to produce than monoclonal antibody treatments if successfully developed and scaled up. According to first author Chen Zilin, an NTU PhD student, the team wanted to test the system against a colorectal cancer model where conventional checkpoint immunotherapy faces challenges, rather than choosing a tumor that already responds well to it.
The approach targets two proteins called PD-1 and PD-L1 that cancer cells exploit to evade immune attack—PD-1 sits on the surface of T cells, while PD-L1 is displayed by tumor cells to trick T cells into a "false handshake" that sends a stop signal, telling the T cell to hold back its attack. Existing checkpoint immunotherapies use monoclonal antibodies to block this interaction from outside the cells, but the NTU approach goes further by reducing the amount of PD-1 and PD-L1 that cells make in the first place. A key limitation of conventional lipid nanoparticles is that only about 1 to 3 per cent of their RNA cargo typically escapes into the cell where it can act, whereas the NTU coacervates are designed to carry large RNA payloads and release them efficiently inside cells. The peptide microdroplets could potentially offer an alternative to lipid nanoparticles, and because the siRNA cargo can be changed, the same platform could potentially be adapted to target other cancers and diseases. The team plans to test the platform in larger animal models to assess safety, dosing, and how long the gene-silencing effect lasts.