An inhaled vaccine using a sugar-based carrier activated lung immune cells and prevented tumor growth in mice, offering a promising approach for long-term protection against lung cancer.
(Nanowerk Spotlight) Despite decades of progress in oncology, lung cancer continues to kill more people each year than any other form of cancer. Its aggressive nature, high recurrence rate, and tendency to spread before symptoms appear have made it especially difficult to treat. Conventional therapies such as surgery, radiation, and chemotherapy remain the standard of care, but they often come with serious side effects and limited long-term benefit.
Even newer targeted therapies only work in a fraction of patients, and cancer often finds ways to resist them. While immunotherapy has transformed treatment for certain cancers, results in lung cancer have been inconsistent. A major barrier has been the inability to trigger a strong and lasting immune response that can both prevent tumors from forming and destroy those that already exist.
Cancer vaccines have offered a potential solution by introducing tumor proteins, known as antigens, into the body to stimulate the immune system to recognize and attack cancer cells. But despite years of research, these vaccines have mostly failed to produce results outside the laboratory. One reason is that most are delivered by injection under the skin, a route that may not be ideal for fighting tumors that grow deep in the lungs. The immune system operates differently in various parts of the body, and what works for the bloodstream or lymph nodes may not work in the lungs.
Researchers have therefore been exploring mucosal vaccination, which targets immune tissue found along moist surfaces such as the lungs. The idea is to deliver the vaccine directly to where the tumor develops. But this strategy has faced major technical obstacles. Delivering antigens into the lungs in a way that ensures they reach the right immune cells, stay intact, and trigger a full immune response is a challenge that has yet to be solved.
Schematic illustration of DDP/LLC nanovaccine designed to prevent the progression of lung cancer. a) Natural dextran was modified into a novel vaccine vector (DDP) for delivering the LLC lysate antigen, the optimal DDP demonstrated the ability to stimulate BMDC maturation by multiple signaling pathways activation. b) The resulting DDP/LLC nanovaccine exhibits remarkable potential to activate immune response, thereby preventing lung cancer progression by inhaled immunization. Compared to traditional subcutaneous immunization, this inhaled immunization strategy demonstrated significant advantages in promoting the maturation and activation of germinal center B cells and Tfh cells in the thoracic lymph node, as well as the upregulation of TRM cells in the lung. Illustration created in BioRender. (Image reprinted with permission by Wiley-VCH Verlag) (click on image to enlarge)
Dextran is known for its safety, biodegradability, and ability to interact with immune cells, but in its native form it is not effective at delivering antigens. To make it suitable as a vaccine carrier, the researchers chemically modified dextran by adding two key components. The first, a molecule called N,N-dimethylethylenediamine, gives the particle a positive charge. This helps it bind to negatively charged antigens. The second, phenylboronic acid, strengthens its interaction with proteins and assists in cellular uptake. The resulting material, called DDP, was optimized to improve both delivery and immune stimulation.
Among different formulations tested, one version with a balanced ratio of modifications showed the strongest ability to activate dendritic cells. These cells serve as the immune system’s scouts. They capture antigens, process them, and present them to other immune cells to launch a response. In experiments using mouse-derived cells, the DDP material stimulated the maturation of dendritic cells and triggered the release of key signaling molecules involved in inflammation and immune activation. The vaccine also activated multiple cellular pathways that are known to drive immune responses.
To test whether this modified dextran could work as part of a functioning vaccine, the researchers combined it with proteins extracted from Lewis lung carcinoma cells, a common mouse model of lung cancer. The proteins and DDP formed nanoparticles small enough to be inhaled. When immune cells were exposed to these particles, they showed strong signs of activation. Dendritic cells processed the tumor proteins, presented them on their surfaces, and communicated with CD8-positive T cells, which are specialized for killing tumor cells.
The vaccine was tested in mice through an inhalation system that delivered the particles directly into the respiratory tract. Mice received three doses over several weeks and were then exposed to tumor cells. Those treated with the inhaled nanovaccine showed a powerful immune response. Half of the mice remained tumor-free after six months.
Even more notably, when the surviving mice were re-exposed to the tumor cells, a third of them resisted the second challenge. This shows that the vaccine induced long-term immune memory, one of the most important goals in cancer immunotherapy.
The study also looked at what types of immune cells were activated by the vaccine. In addition to cytotoxic T cells, which directly kill cancer cells, the vaccine promoted the formation of B cells that mature in lymph nodes and help generate antibodies. A particular focus was placed on germinal center B cells and a group of helper cells known as follicular helper T cells, which support the production of high-affinity antibodies. These types of immune responses are typically difficult to elicit through inhaled vaccination, but they were robust in this case.
One of the most significant findings came from comparing the inhaled vaccine to one delivered by injection under the skin. While both versions activated immune cells in the spleen, only the inhaled vaccine triggered strong responses in the lungs and in nearby lymph nodes. It also produced more tissue-resident memory T cells in the lungs. These are specialized immune cells that remain in a specific tissue, ready to respond quickly if the same threat appears again. Their presence is considered essential for long-lasting protection against tumors that recur or spread locally. Mice that received the vaccine by inhalation developed smaller tumors and survived longer than those vaccinated by injection.
The mechanism of delivery also played a critical role. The nanoparticles entered immune cells using multiple routes and avoided degradation by cellular structures that typically break down foreign materials. This preserved the integrity of the antigens and allowed them to be presented effectively. The vaccine formulation was stable and showed no toxic effects in mouse tissues, including major organs such as the liver, kidney, and spleen.
The ingredients used in the vaccine are readily available and have a history of safe use. The chemical process for creating the modified dextran does not require rare reagents or complicated steps. This makes the technology easier to scale and more likely to meet regulatory requirements for future clinical use.
The findings demonstrate how inhalation-based vaccines can leverage the unique immune environment of the lungs to produce more targeted and durable protection. By using a carefully engineered version of dextran to carry tumor antigens directly into the respiratory system, the study offers a new strategy for lung cancer prevention.
The approach could potentially be adapted to other diseases that affect the lungs, including respiratory infections and metastatic cancers that spread to the lung. It also provides a strong case for investing further in vaccine platforms that deliver immunity at the point of need, rather than relying solely on systemic responses generated through injections.
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