LAUSR

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant cancer with complex genomic variations, and no targetable genomic lesions have been found yet. Super‐enhancers (SEs) have been found to contribute to the continuous and robust oncogenic transcription. Here, histone H3 lysine 27 acetylation (H3K27ac) is profiled in PDAC cell lines to establish SE landscapes. Concurrently, it is also shown that PDAC is vulnerable to the perturbation of the SE complex using bromodomain‐containing protein 4 (BRD4) inhibitor, JQ1, synergized with cyclin‐dependent kinase 7 (CDK7) inhibitor, THZ1. Formulations of hydrophobic l‐phenylalanine‐poly (ester amide) nanoparticles (NPs) with high drug loading of JQ1 and THZ1 (J/T@8P4s) are further designed and developed. J/T@8P4s is assessed for size, encapsulation efficiency, morphology, drug release profiles, and drug uptake in vitro. Compared to conventional free drug formulation, the nanodelivery system dramatically reduces the hepatotoxicity while significantly enhancing the tumor inhibition effects and the bioavailability of incorporated JQ1 and THZ1 at equal doses in a Gemcitabine‐resistant PDAC patient‐derived xenograft (PDX) model. Overall, the present study demonstrates that the J/T@8P4s can be a promising therapeutic treatment against the PDAC via suppression of SE‐associated oncogenic transcription, and provides a strategy utilizing NPs to assist the drug delivery targeting SEs.