Fig. 1: Schematic illustration of PDAC therapy by T-AsiG-CPL-mediated dual modulation of energy and stromal metabolism.
From: Dual rectification of metabolism abnormality in pancreatic cancer by a programmed nanomedicine
T-AsiG-CPL is formulated with cationic lipid (DOTAP), acidic cholesterol (CHEMS), and ionizable lipid (DSPE-PEOz), along with NF-κB inhibitor TPCA-1 and CD71 aptamer-modified siRNA targeting Glut1 (AsiG). TPCA-1 is liberated to the acidic tumor microenvironment (TME) by the pH-sensitive nanosystem (i), reversing the activated PSC to a quiescent state by blocking NF-κB pathway, which diminishes its metabolic support to PDAC cells and suppresses extracellular matrix (ECM) hyperplasia. CD71 aptamer subsequently mediates PDAC cell-targeted delivery of AsiG that is then cleaved by abundant GSH (ii) and releases Glut1 siRNA to disrupt the aerobic glycolysis inside the PDAC cells. Additionally, the inhibition of NF-κB by TPCA-1 curtails the compensatory increase in oxidative phosphorylation (OXPHOS) after glucose limitation in PDAC cells. This multifaceted nano-approach hinders the metabolic crosstalk between PSC and PDAC cells and potentiates the oncotherapy.
