Dual rectification of metabolism abnormality in pancreatic cancer by a programmed nanomedicine

Bowen Wu, Zhiqin Wang, Jingyuan Liu, Naishi Li, Xudong Wang, HaoChen Bai, Chunling Wang, Jian Shi, Saiyang Zhang, Jian Song, Yiye Li () and Guangjun Nie ()
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Bowen Wu: Zhengzhou University
Zhiqin Wang: National Center for Nanoscience and Technology
Jingyuan Liu: National Center for Nanoscience and Technology
Naishi Li: National Center for Nanoscience and Technology
Xudong Wang: National Center for Nanoscience and Technology
HaoChen Bai: National Center for Nanoscience and Technology
Chunling Wang: National Center for Nanoscience and Technology
Jian Shi: National Center for Nanoscience and Technology
Saiyang Zhang: Zhengzhou University
Jian Song: Zhengzhou University
Yiye Li: National Center for Nanoscience and Technology
Guangjun Nie: Zhengzhou University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy characterized by dysregulated energy and stromal metabolism. It is strongly supported by activated pancreatic stellate cells (PSC) which drive excessive desmoplasia and tumor growth via metabolic crosstalk. Herein, a programmed nanosystem is designed to dual rectify the metabolism abnormalities of the PDAC cells, which overexpress glucose transporter 1(GLUT1) and CD71, and the PSC for oncotherapy. The nanosystem is based on a tumor microenvironment-responsive liposome encapsulating an NF-κB inhibitor (TPCA-1) and a CD71 aptamer-linked Glut1 siRNA. TPCA-1 reverses the activated PSC to quiescence, which hampers metabolic support of the PSC to PDAC cells and bolsters the PDAC cell-targeting delivery of the siRNA. Aerobic glycolysis and the following enhancement of oxidative phosphorylation are restrained by the nano-modulation so as to amplify anti-PDAC efficacy in an orthotopic xenograft mouse model, which implies more personalized PDAC treatment based on different energy metabolic profiles.

Date: 2024
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DOI: 10.1038/s41467-024-54963-y

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