A Targeted Octahedral DNA Nanostructure Co-delivers siME3 and Doxorubicin to Enhance Collateral Lethality in ME2-Deficient Pancreatic Cancer.

The genetic characteristics of pancreatic cancer (PC) are being revealed, but treatment strategies based on these profiles are developing slowly. About one-third of PC patients harbor SMAD4 mutations, with its homozygous deletions often accompanied by deletions of the malic enzyme 2 (ME2) gene, leading to upregulation of malic enzyme 3 (ME3) to eliminate reactive oxygen species (ROS). We designed an aptamer-modified octahedral DNA nanostructure for targeted co-delivery of siRNA targeting ME3 (siME3) and doxorubicin (DOX). This nanostructure targets the epidermal growth factor receptor (EGFR) on the membrane of PC cells. Upon internalization, siME3 and DOX are released intracellularly. The siME3 effectively inhibited ME3 expression, diminishing the tumor cells' capacity to clear ROS. Moreover, DOX further increases the level of cellular ROS, and the sustained accumulation of ROS ultimately leads to apoptosis of ME2-deficient PC cells. This targeting nanostructure shows potential for enhancing collateral lethality in this PC subgroup.