Inhalable extracellular vesicle delivery of RNA to treat lung cancer and promote systemic immunity

Lung carcinoma, one of the most prevalent cancers globally, poses a significant challenge due to its low survival rates. Traditional treatments often come with adverse side effects and limited efficacy. However, recent advancements in immunotherapy have shown promise in harnessing the body’s immune system to combat cancer. One such avenue involves the use of cytokines like interleukin-12 (IL-12) as potent tumor suppressors. Despite their potential, systemic administration of these cytokines can lead to off-target toxicity, limiting their effectiveness. Here, we explore a groundbreaking strategy that could revolutionize lung cancer treatment by delivering IL-12 messenger RNA (mRNA) directly to cancer cells via inhalation, thereby minimizing systemic side effects and maximizing therapeutic benefits.

Researchers at Columbia University have developed a novel approach involving the encapsulation of IL-12 mRNA within extracellular vesicles, which are small membrane-bound particles capable of delivering cargo to specific cells. By inhaling these vesicles, the IL-12 mRNA is preferentially taken up by cancer cells in the lungs, allowing for targeted delivery and reducing systemic toxicity.

Once inside the cancer cells, the IL-12 mRNA prompts the production of interferon-γ, a key immune signaling molecule, in both innate and adaptive immune-cell populations. This triggers a robust immune response within the tumor microenvironment, enhancing its immunogenicity and activating cytotoxic immune effector cells. Additionally, the strategy promotes the formation of immune memory, improves antigen presentation, and primes tumor-specific T cells for attack.

Importantly, this localized delivery of IL-12 mRNA has been shown to provide significant protection against tumor rechallenge, indicating its potential as an effective treatment for both primary and metastatic lung tumors. By harnessing the power of the body’s immune system, this innovative therapy offers new hope for patients battling lung cancer.

In vitro characterization of IL-12-Exo and in vivo distribution in LL/2 tumour-bearing mice

Fig. 1

a, Schematic showing IL-12 mRNA loading into HEK-Exo (IL-12-Exo) or liposomes (IL-12-Lipo), followed by nebulized inhalation administration to LL/2 tumour-bearing mouse lungs. LL/2 tumour cells were i.v. injected into C57BL/6 mice for orthotopic lung tumour model establishment. UTR, untranslated region. b,c, NanoSight size distribution analysis (b) and transmission electron microscopy imaging (c) of IL-12-Exo and IL-12-Lipo (experiments were replicated in triplicate). Scale bars, 200 nm. d, Representative ex vivo images and quantitative analysis of mouse major organs that received fluorescence-labelled IL-12-Exo and IL-12-Lipo 24 h postadministration (n = 5 biologically independent mice per group). e, Representative immunostaining images of tumour-bearing mouse lungs. IL-12-Exo and IL-12-Lipo were stained with DiD (grey) before inhalation. LL/2 tumour cells and macrophages were stained with anti-luciferase antibody (green) and anti-F4/80 antibody (red), respectively. Nuclei were stained with DAPI (blue). Scale bar, 100 μm. White arrowheads indicated merged signals of IL-12-Exo or IL-12-Lipo with LL/2 tumour cells, yellow arrowheads indicated merged signals of IL-12-Exo or IL-12-Lipo with macrophages. Experiments were replicated in triplicate. f, Flow cytometry showing cellular uptake percentage of IL-12-Exo or IL-12-Lipo in total lung cells 24 h after drug administration. gj, Flow cytometry showing the proportion of IL-12-Exo or IL-12-Lipo uptake by LL/2 tumour cells (g), macrophages (F4/80+CD11b+) (h), epithelial cells (CD45CD31EpCAM+) (i) and DCs (CD45+CD11c+CD24+) (j), each compared to total lung cells 24 h after drug administration. n = 9 biologically independent mice per group for fh, n = 3 biologically independent mice per group for i,jk,l, The uptake distribution of IL-12-Exo (k) or IL-12-Lipo (l) in various cell types. Experiments were replicated in triplicate. P values were determined by two-way ANOVA post-Bonferroni’s multiple comparison test (d) and two-tailed unpaired Student’s t-test (fj) using GraphPad PRISM software. Exact P values are indicated. Results are presented as means ± s.d. Min., minimum; max., maximum.

The development of this inhalable IL-12 mRNA therapy represents a significant advancement in cancer immunotherapy. By circumventing the limitations of systemic cytokine administration, such as off-target toxicity, this targeted approach holds promise for improving patient outcomes and quality of life. Furthermore, its efficacy against both primary and metastatic tumors underscores its potential as a versatile treatment option for lung cancer patients.

As research continues to uncover the intricate mechanisms of cancer biology, innovative therapies like inhalable IL-12 mRNA offer new avenues for treatment. By harnessing the body’s natural defenses and delivering therapeutic agents directly to cancer cells, this approach represents a promising step forward in the fight against lung carcinoma. With further development and clinical testing, this groundbreaking strategy has the potential to transform the landscape of lung cancer treatment and improve the lives of patients worldwide.

Liu M, Hu S, Yan N, Popowski KD, Cheng K. (2024) Inhalable extracellular vesicle delivery of IL-12 mRNA to treat lung cancer and promote systemic immunity. Nat Nanotechnol [Epub ahead of print]. [abstract]

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