Research Team Develops LNP-circRNA Vaccine, One Drop in The Nose Can Eliminate Lung Tumors

Recently, a research team from Tsinghua University published a research paper titled "Intranasal prime-boost RNA vaccination elicits potent T cell response for lung cancer therapy" in the journal Signal Transduction and Targeted Therapy.

The study used circular RNA (circRNA) encapsulated in lipid nanoparticles (LNP) to induce local mucosal immune responses, thereby developing the world's first intranasal circRNA cancer vaccine. In lung cancer mouse experiments, the vaccine induced a strong anti-tumor T cell response, accurately cleared lung tumors, and reduced systemic adverse reactions commonly associated with intravenous mRNA vaccines. In addition, CAR-T cell responses can be regulated to enhance the therapeutic effect on tumor cells expressing specific tumor-associated antigens.

Overall, the intranasal RNA vaccine strategy represents a new and promising approach to developing RNA vaccines for mucosal malignancies.

Existing cancer vaccines are mostly administered by intramuscular injection or intravenous administration, which can easily cause systemic inflammatory reactions and is difficult to accurately target lung tumors. The research team took a unique approach and chose the nasal mucosa as a breakthrough. This is the first line of defense in the respiratory tract, and 90% of lung cancer originates from the bronchial mucosa. Directly activating immunity here can be called "precision guidance."

The research team has created three core technologies:

1. Super stable circRNA: Compared with traditional linear mRNA, the stability of circular RNA at 37°C is increased by 3 times, thereby greatly prolonging the antigen expression time.

2. Lung-targeted liposomes: Nanoparticles with added cationic lipid DOTAP, like a courier car equipped with GPS, penetrate the nasal mucosa and accurately enrich in the lungs.

3. Dual antigen presentation system: The vaccine can activate dendritic cells to start T cells, and can also be reactivated by alveolar macrophages to form an immune "memory storm".

Figure 1. Intranasal circRNA delivery via lipid nanoparticles initiates protein expression at lung tissues. (Li H, et al., 2025)

In the lung cancer metastasis mouse model:

Prevention mode: After 2 doses of vaccine, tumor cells were injected again 30 days later, and 70% of mice survived tumor-free for a long time.

Treatment mode: Mice with lung metastasis were immunized intranasally 3 times, and the tumor load was reduced by 83%. The median survival period was extended from 18 days to 35 days, almost doubling.

Safety advantage: The level of serum inflammatory factors was only 1/5 of that in the intravenous injection group, completely avoiding the "cytokine storm".

The research team found through single-cell sequencing that after vaccination, cDC1 dendritic cells acted as antigens expressed by the vaccine to activate killer T cells. Alveolar macrophages continued to enhance T cell activity. Memory T cells accounted for 42%, a 3-fold increase over the control group. In addition, the vaccine also synergized with CAR-T cells, causing CAR-T cells to expand 15 times and increase their ability to penetrate tumors by 200%.