Modeling lung adenocarcinoma using layer-by-layer nanoparticles mitigates innate immune cell activation

Lung adenocarcinoma, a major cause of cancer deaths, is often caused by mutations in the KRAS and p53 genes. Traditionally, researchers have created mice with these genetic alterations using viral vectors to introduce the necessary mutations. However, these viral particles can infect and activate immune cells, potentially skewing the results of studies examining the interaction between tumors and the immune system.

To address this issue, scientists have developed a layer-by-layer (LbL) polyplex platform. This platform utilizes PBAE polymers layered with PLD to deliver Cre mRNA to the lungs without triggering a response from the immune system. PLD-coated nanoparticles (PLD-NPs) have been shown to effectively encapsulate mRNA and transfect cells in vitro, even after being freeze-dried and stored for extended periods.

When used in genetically engineered mice with KRAS and p53 mutations, the PLD-NPs successfully induced lung adenocarcinomas that closely resemble human tumors in terms of histopathology. Importantly, the use of PLD-NPs did not infect or activate dendritic cells and alveolar macrophages, which are types of innate immune cells. In contrast, viral delivery methods such as lentiviral (LV) and adenoviral vectors led to long-term upregulation of antigen presentation and costimulatory machinery in lung-resident myeloid cells, resulting in persistent immune activation.

By separating tumor initiation from innate immune activation, this LbL polyplex platform enables researchers to study tumor-immune dynamics with greater accuracy, particularly for non-inflammatory types of lung cancer.