Abstract microRNA (miRNA) dysregulation influences critical molecular pathways involved in tumor progression in a wide range of cancer types. Therefore, modulating miRNA levels in cancer cells as a novel therapeutic approach has promising potential in cancer treatment. In our parent NCI project, we proposed to develop a nanoparticle formulation of miRNA-216a as an early intervention for pancreatic cancer. Specifically, we aim to engineer pancreas-targeting nanoparticles to restore the miRNA-216a level at the pancreas at the early stage of pancreatic cancer development. To achieve this goal, we combine in vitro and in vivo screening to identify formulations that can efficiently delivery RNAs to pancreas. Although thousands of nanoformulations of nucleic acids have been synthesized and have shown good in vitro transfection, excellent in vitro delivery efficiency often fails to translate in vivo. To address this challenge, we propose to adopt a novel high throughput in vivo screening approach to simultaneously measure the tumor delivery efficiency of a library of barcoded nanoformulations of miRNA. Our central hypothesis is that in vivo high throughput screening of barcoded nanoparticles can lead to the identification of formulations that selectively deliver miRNAs to the tumor. As nanoparticle in vitro screening results often yield poor predictions for their in vivo delivery efficiency, the results of this study will have the potential to uncover the underlying mechanism of poor in vitro-in in vivo correlation, leading to a better understanding of nanoparticle in vivo targeting behaviors.