Systemic Delivery of an mRNA-Encoding, Tumor-Activated Interleukin-12 Lock to Eliminate Tumors and Avoid Immune-Related Adverse Events

Interleukin-12 (IL-12) is a robust proinflammatory cytokine that activates immune cells, such as T cells and natural killer cells, to induce antitumor immunity. However, the clinical application of recombinant IL-12 has been limited by systemic immune-related adverse events (irAEs) and rapid degradation. To address these challenges, we employed mRNA technology to encode a tumor-activated IL-12 "lock" fusion protein that offers both therapeutic efficacy and systemic safety. Lock-IL-12 mRNA encodes a sequence consisting of the IL-12 receptor-binding domain, a matrix metalloproteinase-2 (MMP-2)-cleavable linker, and two IL-12 subunits. Systemic delivery of the mRNA via lipid nanoparticles (LNPs) enables widespread systemically expression of Lock-IL-12 protein in the locked state, and maintaining an inactive state during circulation. Upon reaching the MMP-2-rich tumor microenvironment (TME), the fusion protein undergoes cleavage, activating IL-12 to initiate a powerful antitumor immune response. This strategy represents a promising approach for cytokine-based tumor therapy, combining efficient delivery with minimal systemic toxicity.

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Publication Details

Journal
Nano Letters
Published
2025-09-10
DOI
https://doi.org/10.1021/acs.nanolett.5c03454
Citations
2
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
2.09
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article

Systemic Delivery of an mRNA-Encoding, Tumor-Activated Interleukin-12 Lock to Eliminate Tumors and Avoid Immune-Related Adverse Events

Dailiang Zhang, Ting Fu, Lizhuan Zhang, Weihong Tan et al.
2 citations
Nano Letters
CAR-T cell therapy research
2.09
article

Systemic Delivery of an mRNA-Encoding, Tumor-Activated Interleukin-12 Lock to Eliminate Tumors and Avoid Immune-Related Adverse Events

Dailiang Zhang, Ting Fu, Lizhuan Zhang, Weihong Tan, Sitao Xie, Zhen Du, Cheng Cui, Ding Ding, Juncai Li, Xiangsheng Liu, Minhui Su, Haoran Jia, Mengyuan Jiang, Yang Sun, Cai Yang, Yuying Yang
article en
2 citations

Abstract

Interleukin-12 (IL-12) is a robust proinflammatory cytokine that activates immune cells, such as T cells and natural killer cells, to induce antitumor immunity. However, the clinical application of recombinant IL-12 has been limited by systemic immune-related adverse events (irAEs) and rapid degradation. To address these challenges, we employed mRNA technology to encode a tumor-activated IL-12 "lock" fusion protein that offers both therapeutic efficacy and systemic safety. Lock-IL-12 mRNA encodes a sequence consisting of the IL-12 receptor-binding domain, a matrix metalloproteinase-2 (MMP-2)-cleavable linker, and two IL-12 subunits. Systemic delivery of the mRNA via lipid nanoparticles (LNPs) enables widespread systemically expression of Lock-IL-12 protein in the locked state, and maintaining an inactive state during circulation. Upon reaching the MMP-2-rich tumor microenvironment (TME), the fusion protein undergoes cleavage, activating IL-12 to initiate a powerful antitumor immune response. This strategy represents a promising approach for cytokine-based tumor therapy, combining efficient delivery with minimal systemic toxicity.

Nano LettersVol. 25(38)
Hunan University (CN), Shanghai Jiao Tong University (CN), Chinese Academy of Sciences (CN), Renji Hospital (CN), Zhejiang Cancer Hospital (CN), Theranostics (New Zealand) (NZ), Institute of Molecular Medicine (IN), State Key Laboratory of Chemobiosensing and Chemometrics (CN)
Openalex Percentile: Top 10%
CAR-T cell therapy research
2.09
DOISourceOpenAlex
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