Cell-specific metabolic reprogramming of tumors for bioactivatable ferroptosis therapy

• Main Authors: Li, Yanan, Li, Menghuan, Liu, Li, Xue, Chencheng, Fei, Yang, Wang, Xuan, Zhang, Yuchen, Cai, Kaiyong, Zhao, Yanli, Luo, Zhong
• Other Authors: School of Physical and Mathematical Sciences
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Chemistry::Biochemistry; Cancer Therapy; Bioorthogonal Tumor Targeting
• Online Access: https://hdl.handle.net/10356/162296
• Institution: Nanyang Technological University

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.