An autocatalytic multicomponent DNAzyme nanomachine for tumor-specific photothermal therapy sensitization in pancreatic cancer

Jiaqi Yan, Xiaodong Ma, Danna Liang, Meixin Ran, Dongdong Zheng, Xiaodong Chen, Shichong Zhou, Weijian Sun (), Xian Shen () and Hongbo Zhang ()
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Jiaqi Yan: The First Affiliated Hospital of Wenzhou Medical University
Xiaodong Ma: Åbo Akademi University
Danna Liang: The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University
Meixin Ran: The First Affiliated Hospital of Wenzhou Medical University
Dongdong Zheng: Fudan University Shanghai Cancer Center
Xiaodong Chen: The First Affiliated Hospital of Wenzhou Medical University
Shichong Zhou: Fudan University Shanghai Cancer Center
Weijian Sun: The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University
Xian Shen: The First Affiliated Hospital of Wenzhou Medical University
Hongbo Zhang: The First Affiliated Hospital of Wenzhou Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Multicomponent deoxyribozymes (MNAzymes) have great potential in gene therapy, but their ability to recognize disease tissue and further achieve synergistic gene regulation has rarely been studied. Herein, Arginylglycylaspartic acid (RGD)-modified Distearyl acylphosphatidyl ethanolamine (DSPE)-polyethylene glycol (PEG) (DSPE-PEG-RGD) micelle is prepared with a DSPE hydrophobic core to load the photothermal therapy (PTT) dye IR780 and the calcium efflux pump inhibitor curcumin. Then, the MNAzyme is distributed into the hydrophilic PEG layer and sealed with calcium phosphate through biomineralization. Moreover, RGD is attached to the outer tail of PEG for tumor targeting. The constructed nanomachine can release MNAzyme and the cofactor Ca2+ under acidic conditions and self-assemble into an active mode to cleave heat shock protein (HSP) mRNA by consuming the oncogene miRNA-21. Silencing miRNA-21 enhances the expression of the tumor suppressor gene PTEN, leading to PTT sensitization. Meanwhile, curcumin maintains high intracellular Ca2+ to further suppress HSP-chaperone ATP by disrupting mitochondrial Ca2+ homeostasis. Therefore, pancreatic cancer is triple-sensitized to IR780-mediated PTT. The in vitro and in vivo results show that the MNAzyme-based nanomachine can strongly regulate HSP and PTEN expression and lead to significant pancreatic tumor inhibition under laser irradiation.

Date: 2023
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DOI: 10.1038/s41467-023-42740-2

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