Inhalable extracellular vesicle delivery of IL-12 mRNA to treat lung cancer and promote systemic immunity

Abstract

Lung carcinoma is one of the most common cancers and has one of the lowest survival rates in the world. Cytokines such as interleukin-12 (IL-12) have demonstrated considerable potential as robust tumour suppressors. However, their applications are limited due to off-target toxicity. Here we report on a strategy involving the inhalation of IL-12 messenger RNA, encapsulated within extracellular vesicles. Inhalation and preferential uptake by cancer cells results in targeted delivery and fewer systemic side effects. The IL-12 messenger RNA generates interferon-γ production in both innate and adaptive immune-cell populations. This activation consequently incites an intense activation state in the tumour microenvironment and augments its immunogenicity. The increased immune response results in the expansion of tumour cytotoxic immune effector cells, the formation of immune memory, improved antigen presentation and tumour-specific T cell priming. The strategy is demonstrated against primary neoplastic lesions and provides profound protection against subsequent tumour rechallenge. This shows the potential for locally delivered cytokine-based immunotherapies to address orthotopic and metastatic lung tumours. Cytokine interleukin-12 (IL-12) has potential for tumour suppression yet off-target effects limit potential applications. Here the authors report on the delivery of IL-12 mRNA encapsulated in extracellular vesicles to lungs via inhalation and demonstrate the immunotherapeutic potential of targeted cytokine mRNA therapy.