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.

肺癌是最常见的癌症之一，也是世界上存活率最低的癌症之一。白细胞介素 12 (IL-12) 等细胞因子已显示出作为强大的肿瘤抑制剂的巨大潜力。然而，由于脱靶毒性，它们的应用受到限制。在这里，我们报告了一种涉及吸入封装在细胞外囊泡内的 IL-12 信使 RNA 的策略。吸入和癌细胞优先摄取可实现靶向递送并减少全身副作用。IL-12 信使 RNA 在先天性和适应性免疫细胞群中产生干扰素 γ。因此，这种激活会在肿瘤微环境中引发强烈的激活状态并增强其免疫原性。免疫反应的增强导致肿瘤细胞毒性免疫效应细胞的扩增、免疫记忆的形成、抗原呈递的改善和肿瘤特异性T细胞的启动。该策略已被证明可以对抗原发性肿瘤病变，并为随后的肿瘤再攻击提供深刻的保护。这显示了局部递送的基于细胞因子的免疫疗法治疗原位和转移性肺肿瘤的潜力。