mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy

Fengqiao Li, Xue-Qing Zhang (), William Ho, Maoping Tang, Zhongyu Li, Lei Bu and Xiaoyang Xu ()
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Fengqiao Li: New Jersey Institute of Technology
Xue-Qing Zhang: Shanghai Jiao Tong University
William Ho: New Jersey Institute of Technology
Maoping Tang: Shanghai Jiao Tong University
Zhongyu Li: New Jersey Institute of Technology
Lei Bu: NYU Grossman School of Medicine
Xiaoyang Xu: New Jersey Institute of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Synergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold tumors, yet current treatments often fail to induce a cascade of cancer-immunity cycle for effective antitumor immunity. Gasdermin-mediated pyroptosis is a newly discovered mechanism in cancer immunotherapy; however, cleavage in the N terminus is required to activate pyroptosis. Here, we report a single-agent mRNA nanomedicine-based strategy that utilizes mRNA lipid nanoparticles (LNPs) encoding only the N-terminus of gasdermin to trigger pyroptosis, eliciting robust antitumor immunity. In multiple female mouse models, we show that pyroptosis-triggering mRNA/LNPs turn cold tumors into hot ones and create a positive feedback loop to promote antitumor immunity. Additionally, mRNA/LNP-induced pyroptosis sensitizes tumors to anti-PD-1 immunotherapy, facilitating tumor growth inhibition. Antitumor activity extends beyond the treated lesions and suppresses the growth of distant tumors. We implement a strategy for inducing potent antitumor immunity, enhancing immunotherapy responses in immunologically cold tumors.

Date: 2023
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DOI: 10.1038/s41467-023-39938-9

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