Nitric oxide-powered nanomotors restore tumor blood and lymphatic vessels, enabling deeper T-cell infiltration and stronger immune responses that suppress tumor growth and promote lasting immune memory.
(Nanowerk Spotlight) Solid tumors are notoriously difficult to treat with immunotherapy. One reason is that immune cells, particularly T cells, often fail to reach the tumor’s interior in sufficient numbers. These immune cells typically travel through blood vessels, but the vasculature in tumors is abnormal. Tumor-associated blood vessels are often compressed, misshapen, and leaky, with poor flow and high internal pressure.
These structural flaws not only prevent T cells from entering but also block the delivery of drugs, oxygen, and nutrients. Tumor lymphatic vessels are also dysfunctional, which hinders the drainage of immune signals and antigen-presenting cells. Together, these problems form a physical and biological barrier that shields tumors from immune attack.
Past attempts to fix this relied largely on antiangiogenic therapies, which are drugs that block blood vessel growth by targeting vascular endothelial growth factors. These treatments often come with side effects such as hypertension or increased risk of clotting, and they do not reliably improve immune cell access to tumors. More recent work has explored an alternative strategy that focuses on restructuring existing tumor vessels to restore function instead of eliminating them. The aim is to create a more organized vascular network that supports both drug delivery and immune infiltration.
Alongside these efforts, micro- and nanoscale technologies have opened new possibilities. Nanomaterials can be engineered to penetrate tumors, respond to chemical cues, and reshape the tumor environment from within. Among these tools, nanomotors are gaining attention. These are tiny particles capable of autonomous movement that can push through biological barriers where conventional drugs often fail, especially when designed to respond to the tumor’s own internal chemistry.
Schematic of the nitric oxide-powered HAM nanomotor. The particle consists of a hollow gold shell with two chemically distinct sides: one modified with L-arginine, which produces nitric oxide in response to reactive oxygen species, and the other with a maleimide group that captures tumor antigens. Once released from its lipid carrier and activated by near-infrared light, the nanomotor penetrates tumor tissue, kills cancer cells through heat and oxidative stress, captures whole-tumor antigens, and helps restore damaged blood vessels to support deeper T-cell infiltration and immune activation. (Image: Reprinted from DOI:10.1002/advs.202512090, CC BY) (click on image to enlarge)
The researchers developed a particle called HAM, short for hollow gold Janus nanomotor. It consists of a tiny gold shell with an empty interior, which makes it lightweight and responsive to external triggers. Its two-sided, or “Janus,” structure is key to its function: one side is coated with L-arginine, a molecule that generates nitric oxide when it reacts with reactive oxygen species found in tumors. The other side is coated with maleimide groups, which can bind to proteins released by dying cancer cells.
This asymmetry allows the particle to move in a directed way, powered by chemical reactions in the tumor environment. When activated by near-infrared light, the gold shell produces heat and reactive oxygen, killing nearby tumor cells and releasing a wide range of antigens. These are then captured by the nanomotor and presented to the immune system, helping to stimulate a stronger T-cell response against the tumor.
The nitric oxide released by the nanomotor serves two main functions. First, it helps normalize tumor blood vessels by increasing the coverage of pericytes, which are support cells that stabilize vessel walls. This results in more structured and functional vasculature that allows immune cells to enter more effectively. Second, nitric oxide acts as the chemical fuel for the nanomotor. In the presence of reactive oxygen, the arginine on the nanomotor generates nitric oxide, which drives its movement and allows it to travel deeper into the tumor tissue.
To improve stability and targeting, the HAM nanomotors were encapsulated in a lipid-based carrier modified with peptides that bind to molecules found on tumor blood vessels. These carriers, called HAM-RN, remain intact during circulation and release the nanomotors only when exposed to laser light at the tumor site. Experiments in mouse models of melanoma (B16F10) and breast cancer (4T1) showed that HAM-RN accumulates effectively in tumors and penetrates more deeply than particles without the nanomotor function.
The researchers also introduced a second nanoparticle system containing VEGFC, a protein that promotes the growth of lymphatic vessels. These vessels play an important role in transporting dendritic cells, which carry tumor antigens to lymph nodes where T cells are activated. When used together, the HAM-RN and VEGFC nanoparticles reconstructed both blood and lymphatic vessels in the tumor environment. This combination improved immune cell entry into tumors and also supported more effective T-cell priming in the lymph nodes.
In mice treated with the combined therapy, the number of tumor-infiltrating CD8+ T cells increased significantly. In some cases, the proportion rose from below one percent to over 27 percent. These tumors also showed higher levels of immune-activating signals such as interferon-gamma and tumor necrosis factor, along with reduced levels of immune-suppressive cytokines like TGF-beta. The therapy also increased the population of memory T cells, which are needed for long-term immune protection.
The study included several tests of safety and tolerability. The nanomotors did not cause detectable damage to red blood cells or vital organs in mice. Body weight remained stable, and key inflammation markers in the blood stayed within normal ranges. Importantly, the heating effect that triggers particle release and cell killing was only activated at the tumor site using externally applied near-infrared light.
The authors also examined how nitric oxide influences blood vessel structure at the molecular level. They found that NO increases the expression of ZBTB46, a protein linked to more organized vasculature in tumors. This supports the idea that the nanomotors are not just clearing space or improving flow, but actively reprogramming the endothelial cells that form the vessel lining.
Although the results are promising, there are several technical challenges to address. The method depends on laser light to activate the particles, which may be hard to deliver in deep or less accessible tumors in patients. The long-term fate of gold particles in the body is also a consideration, although using hollow structures may reduce accumulation. These findings were demonstrated in mice, so further work is needed to test whether the effects hold up in more complex tumor models and eventually in human trials.
Still, the core idea of the study is compelling. Rather than targeting tumor cells directly, the approach focuses on reshaping the physical structure of the tumor environment to allow immune cells to enter and function. By combining vessel normalization with antigen capture and immune activation, the researchers present a multifaceted strategy that could address one of the most persistent problems in cancer immunotherapy.
This work highlights the value of engineered nanomaterials that respond to chemical signals in the tumor and perform more than one function. These nitric oxide-powered nanomotors penetrate tumors, normalize blood vessels, trigger antigen release, and promote immune activation, all in a coordinated sequence. While more work is needed before clinical application, the study outlines a direction for immunotherapy that integrates structural, chemical, and biological strategies in a single platform.
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