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

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.