Journal Article

AS1411 Aptamer-Conjugated Liposomal siRNA Targeting MTA2 Suppresses PI3K/AKT Signaling in Pancreatic Cancer Cells

Kwak, Minseo, Jin, Hyesoo, Hua, Truong Chinh, Lee, Jongsam, Kim, Dong-Eun

2025

Overview

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies due to late diagnosis, poor drug penetration, and intrinsic chemoresistance. Targeted delivery strategies are urgently needed to enhance therapeutic precision while minimizing systemic toxicity. Here, we developed an AS1411 aptamer-functionalized liposomal platform encapsulating siRNA against metastasis-associated protein 2 (MTA2), a chromatin remodeling factor that suppresses the tumor suppressor PTEN and activates PI3K/AKT signaling. The AS1411 aptamer, which binds nucleolin overexpressed on PDAC cells, was conjugated to cationic liposomes via copper-free click chemistry. The resulting AS1411-Lipm[siRNA] exhibited high siRNA encapsulation efficiency, selective uptake by nucleolin-positive PDAC cells, and enhanced endosomal escape. Treatment of MIA PaCa-2 cells with AS1411-Lipm[siRNA] significantly reduced MTA2 expression by ~60%, substantially restored PTEN, and inhibited AKT phosphorylation by ~50%, leading to decreased cell viability, impaired migration by ~75%, and increased apoptosis by ~35%, while sparing nucleolin-negative cells. These findings highlight AS1411-Lipm[siRNA] as a promising platform for selective siRNA delivery and potent molecular inhibition in PDAC therapy.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Apoptosis - drug effects / Aptamers, Nucleotide - chemistry / Cancer therapies / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - metabolism / Cell Line, Tumor / Cell Survival - drug effects / Chemotherapy / Cholesterol / Efficiency / Gene Expression Regulation, Neoplastic - drug effects / Health aspects / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Humans / Lipids / Liposomes - chemistry / Medical prognosis / Metastasis / Nucleolin / Oligodeoxyribonucleotides - chemistry / Oligodeoxyribonucleotides - pharmacology / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Phosphatidylinositol 3-Kinases - metabolism / Proto-Oncogene Proteins c-akt - metabolism / PTEN Phosphohydrolase - metabolism / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - genetics / Repressor Proteins - metabolism / RNA, Small Interfering - genetics / RNA-Binding Proteins - metabolism / Signal Transduction - drug effects / Trans-Activators / Transmission electron microscopy