Peptide-Modified Lipid Nanoparticles Boost The Antitumor Efficacy Of Rna Therapeutics

RNA therapeutics have emerged as a promising avenue for cancer treatment due to their ability to precisely regulate cancer-related genes. While lipid nanoparticles (LNPs) are currently the most advanced non-viral, clinically approved vectors for RNA therapeutics, their anti-cancer efficacy is limited by accumulation in the liver after systemic administration. Hence, there is an urgent need to enhance specificity of LNPs delivery strictly to cancer cells.  

We modified the FDA approved Onpattro formulation of LNPs (MC3-LNPs) with a CD44- targeting peptide to allow for co-delivery of small interfering RNAs (siRNAs). 

We showed that peptide functionalized AKPC-LNPs significantly improved targeting cancer cells. After encapsulation of siYAP/TAZ, AKPC-siYT-LNPs induced potent gene silencing, leading to apoptosis, and cell death in breast and prostate cancer cells and spheroids. In breast cancer cells xenografted zebrafish model, systemic administration of AKPC-siYT nanoparticles caused robust silencing of YAP/TAZ and downstream genes, enhancing tumor suppression compared to unmodified MC3-LNPs. Importantly, AKPC-siYT-LNPs attenuated growth of patient-derived prostate cancer organoids and mouse xenografts. 

To enhance the precision of gene editing in melanoma, we utilized CD44-peptide-modified AKPC-LNPs for targeted delivery of CRISPR/Cas9 and guided RNA against polo-like kinase 1 (sgPLK1). Our approach led to enhanced targeting and gene editing resulting in significant inhibition of tumor growth in both in vitro and in vivo skin melanoma models. 

Overall, we provide a highly efficient lipid nanoparticle for targeted delivery of interfering RNAs and Cas9-sgRNA therapeutics, paving the way for more precise and effective cancer treatments.