Targeted LNPs deliver IL-15 superagonists mRNA for precision cancer therapy

Juntao Yu; Qian Li; Chaoting Zhang; Qiu Wang; Shenggen Luo; Xiaona Wang; Rongkuan Hu; Qiang Cheng

doi:10.1016/j.biomaterials.2024.123047

Targeted LNPs deliver IL-15 superagonists mRNA for precision cancer therapy

Biomaterials. 2024 Dec 24:317:123047. doi: 10.1016/j.biomaterials.2024.123047. Online ahead of print.

Authors

Juntao Yu¹, Qian Li², Chaoting Zhang³, Qiu Wang², Shenggen Luo¹, Xiaona Wang¹, Rongkuan Hu⁴, Qiang Cheng⁵

Affiliations

¹ Starna Therapeutics Co., Ltd., Suzhou, 215123, China.
² Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, 100871, China.
³ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
⁴ Starna Therapeutics Co., Ltd., Suzhou, 215123, China. Electronic address: hurongkuan@starnatx.com.
⁵ Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, 100871, China; Beijing Advanced Center of RNA Biology (BEACON), Peking University, Beijing, 100871, China. Electronic address: qiangcheng@pku.edu.cn.

PMID: 39742840
DOI: 10.1016/j.biomaterials.2024.123047

Abstract

Interleukin-15 (IL-15) emerges as a promising immunotherapeutic candidate, but the therapeutic utility remains concern due to the unexpected systematic stress. Here, we propose that the mRNA lipid nanoparticle (mRNA-LNP) system can balance the issue through targeted delivery to increase IL-15 concentration in the tumor area and reduce leakage into the circulation. In the established Structure-driven TARgeting (STAR) platform, the LNP^Local and LNP^Lung can effectively and selectively deliver optimized IL-15 superagonists mRNAs to local and lungs, respectively, in relevant tumor models. As a result, such superagonists exhibited well-balanced efficacy and side-effects, demonstrating the better anti-tumor activity, less systematic exposure, and less cytokine related risks. We finally verified the selective delivery and well tolerability of LNP^Lung in non-human primates (NHPs), confirming the potential for clinical application. This finding provides new potentials for cancers treatment on lung cancers or lung metastasis cancers.

Keywords: Cytokine therapy; IL-15 superagonists; Lipid nanoparticles; Lung-targeting; mRNA delivery.