Journal
ACS NANO
Volume 16, Issue 3, Pages 3965-3984Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c09480
Keywords
bioorthogonal tumor targeting; cancer therapy; ferritinophagy; ferroptosis; metabolic labeling
Categories
Funding
- National Natural Science Foundation of China [32122048, 11832008, 92059107, 51825302]
- Chongqing Graduate Scientific Research and Innovation Program [cYB20047, cYS20043]
- Fundamental Research Funds for the Central Universities [2021CDJLXB001, 2021CDJZYJH-002, 2020CDJYGZL009]
- Chongqing Outstanding Young Talent Supporting Program [cstc2021ycjh-bgzxm0124]
- Natural Science Foundation of Chongqing Municipal Government [cstc2020jcyj-msxmX0834, cstc2021jcyj-jqX0022]
- Singapore National Research Foundation [NRF-NRFI2018-03, CRP26-2021-0058]
- Returning Overseas Scholar Innovation Program [CX2018062, CX2021098, CX2020045]
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This study reports a combinational strategy based on clinically tested constituents to selectively induce ferroptosis in metabolically reprogrammed tumor cells, providing a generally applicable therapy.
Ferroptosis is a nonapoptotic iron-dependent cell death pathway with a significant clinical potential, but its translation is impeded by lack of tumor-specific ferroptosis regulators and aberrant tumor iron metabolism. Herein, we report a combinational strategy based on clinically tested constituents to selectively induce ferroptosis in metabolically reprogrammed tumor cells through cooperative GPX4-inhibition and ferritinophagy-enabled Fe2+ reinforcement. Azido groups were first introduced on tumor cells using biocompatible long-circulating self-assemblies based on polyethylene glycol-disulfide-N-azidoacetyl-D-mannosamine via metabolic glycoengineering. The azido-expressing tumor cells could specifically react with dibenzocyclooctyne-modified disulfide-bridged nanoassemblies via bioorthogonal click reactions, where the nanoassemblies were loaded with ferroptosis inducer RSL3 and ferritinophagy initiator dihydroartemisinin (DHA) and could release them in a bioresponsive manner. DHA-initiated ferritinophagy could degrade intracellular ferritin to liberate stored iron species and cooperate with the RSL3-mediated GPX4-inhibition for enhanced ferroptosis therapy. This tumor-specific ferroptosis induction strategy provides a generally applicable therapy with enhanced translatability, especially for tumors lacking targetable endogenous receptors.
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