MOFs-based nanoagent enables dual mitochondrial damage in synergistic antitumor therapy via oxidative stress and calcium overload

Weier Bao, Ming Liu, Jiaqi Meng, Siyuan Liu, Shuang Wang, Rongrong Jia, Yugang Wang, Guanghui Ma (), Wei Wei () and Zhiyuan Tian ()
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Weier Bao: University of Chinese Academy of Sciences
Ming Liu: University of Chinese Academy of Sciences
Jiaqi Meng: University of Chinese Academy of Sciences
Siyuan Liu: University of Chinese Academy of Sciences
Shuang Wang: Chinese Academy of Sciences
Rongrong Jia: Shanghai Jiao Tong University School of Medicine
Yugang Wang: Shanghai Jiao Tong University School of Medicine
Guanghui Ma: Chinese Academy of Sciences
Wei Wei: Chinese Academy of Sciences
Zhiyuan Tian: University of Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Targeting subcellular organelle with multilevel damage has shown great promise for antitumor therapy. Here, we report a core-shell type of nanoagent with iron (III) carboxylate metal-organic frameworks (MOFs) as shell while upconversion nanoparticles (UCNPs) as core, which enables near-infrared (NIR) light-triggered synergistically reinforced oxidative stress and calcium overload to mitochondria. The folate decoration on MOFs shells enables efficient cellular uptake of nanoagents. Based on the upconversion ability of UCNPs, NIR light mediates Fe3+-to-Fe2+ reduction and simultaneously activates the photoacid generator (pHP) encapsulated in MOFs cavities, which enables release of free Fe2+ and acidification of intracellular microenvironment, respectively. The overexpressed H2O2 in mitochondria, highly reactive Fe2+ and acidic milieu synergistically reinforce Fenton reactions for producing lethal hydroxyl radicals (•OH) while plasma photoacidification inducing calcium influx, leading to mitochondria calcium overload. The dual-mitochondria-damage-based therapeutic potency of the nanoagent has been unequivocally confirmed in cell- and patient-derived tumor xenograft models in vivo.

Date: 2021
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DOI: 10.1038/s41467-021-26655-4

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