A Multiscale Model to Identify Limiting Factors in Nanoparticle-Based miRNA Delivery for Tumor Inhibition.

MicroRNA-based gene therapy for cancer treatment via nanoparticles (NPs) requires navigation of multiple physical and physiological barriers in order to efficiently deliver the miRNAs to the cancer cell cytoplasm. We here present a mathematical model to investigate the variability associated with tumor, NP, and miRNA characteristics, and identify the limiting factors in miRNA delivery to tumors. Through global parameter analysis, the miRNA release rate from NPs and NP degradability were found to have the most significant impact on cytosolic accumulation of miRNAs. These NP properties can be fine-tuned in order to optimize the delivery system for enhancing the efficacy of miRNA-based therapy.Clinical Relevance-Understanding the effect of nanoparticle, tumor, and miRNA characteristics in governing the efficacy of miRNA-based cancer therapy will support its clinical translation.