A Targeted\nOctahedral DNA Nanostructure Co-delivers\nsiME3 and Doxorubicin to Enhance Collateral Lethality in ME2-Deficient\nPancreatic Cancer

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