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

Weier Bao,Siyuan Liu,Shuang Wang,Rongrong Jia,Guanghui Ma,Wei Wei,Ming Liu,Yugang Wang,Zhiyuan Tian,Jiaqi Meng

doi:10.1038/s41467-021-26655-4

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.

Highlights

Targeting subcellular organelle with multilevel damage has shown great promise for antitumor therapy
Owing to the vital physiological roles of mitochondria, which is essential for cell survival and proliferation, strategies capable of activating multilevel mitochondrial damage pathways via spatiotemporally controllable manner are promising for antitumor treatments with desired precision and enhanced therapeutic index
We presented a type of metal-organic frameworks (MOFs)-based FMUP nanoagent that enables NIR light-triggered two distinct mechanisms, namely oxidative stress based on Fenton reactions and calcium overload originating from intracellular acidification, with both of them contributing to the mitochondria-dysfunction-associated eradication of tumor cells

Summary

Introduction

Targeting subcellular organelle with multilevel damage has shown great promise for antitumor therapy. The traditional single-modality antitumor strategy, such as chemotherapy and radiotherapy, generally encounters challenges such as adverse side effects and limited therapeutic efficacy[1,2,3,4] These challenges highlight the vital significance of developing modalities capable of spatiotemporally controllably imparting multilevel damage to specific targets essential for tumor cell survival and proliferation[5]. Besides the feature in terms of light-assisted simultaneously triggering multilevel antitumor mechanisms, the ability to guide antitumor action to vital subcellular organelles that are essential for cell survival and proliferation is unequivocally a key enabling factor for maximizing the overall therapeutic potency. For site-specific attack of mitochondria, the chemodynamic therapy (CDT) based on oxidative stress of OH species is characterized with unequivocal superiority owing to its underlying action mechanism[17]. CDT holds great promise for antitumor treatment based on the site-specific mitochondrial damage, several major impediments need to be overcome for enabling it practicality

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Results

Conclusion