Journal Article

Carrier‐Free Self‐Assembly Nano‐Sonosensitizers for Sonodynamic‐Amplified Cuproptosis‐Ferroptosis in Glioblastoma Therapy

Lin, Yuanxiang, Ding, Chengyu, Kang, Dezhi, Tian, Yu, Pan, Yuanbo, Zou, Jianhua, Huang, Wen, Yan, Lingjun, Chen, Xiaoyuan, Huang, Wei, Zhu, Yang, Fang, Wenhua, Wu, Tiantian, Cheng, Junjie, Niu, Xuegang

2024

Overview

Cuproptosis is a newly discovered form of programmed cell death significantly depending on the transport efficacy of copper (Cu) ionophores. However, existing Cu ionophores, primarily small molecules with a short blood half‐life, face challenges in transporting enough amounts of Cu ions into tumor cells. This work describes the construction of carrier‐free nanoparticles (Ce6@Cu NPs), which self‐assembled by the coordination of Cu2+ with the sonosensitizer chlorin e6 (Ce6), facilitating sonodynamic‐triggered combination of cuproptosis and ferroptosis. Ce6@Cu NPs internalized by U87MG cells induce a sonodynamic effect and glutathione (GSH) depletion capability, promoting lipid peroxidation and eventually inducing ferroptosis. Furthermore, Cu+ concentration in tumor cells significantly increases as Cu2+ reacts with reductive GSH, resulting in the downregulation of ferredoxin‐1 and lipoyl synthase. This induces the oligomerization of lipoylated dihydrolipoamide S‐acetyltransferase, causing proteotoxic stress and irreversible cuproptosis. Ce6@Cu NPs possess a satisfactory ability to penetrate the blood‐brain barrier, resulting in significant accumulation in orthotopic U87MG‐Luc glioblastoma. The sonodynamic‐triggered combination of ferroptosis and cuproptosis in the tumor by Ce6@Cu NPs is evidenced both in vitro and in vivo with minimal side effects. This work represents a promising tumor therapeutic strategy combining ferroptosis and cuproptosis, potentially inspiring further research in developing logical and effective cancer therapies based on cuproptosis. The carrier‐free self‐assembled Ce6@Cu nanoparticles are fabricated for sonodynamic‐therapy involving cuproptosis and ferroptosis. Ce6@Cu NPs show sonodynamic effect and glutathione depletion capability, promoting ferroptosis. Furthermore, the elevated copper concentration induces the downregulation of ferredoxin‐1, lipoyl synthase, and the oligomerization of lipoylated dihydrolipoamide S‐acetyltransferase, causing proteotoxic stress, and cuproptosis.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Animals / Brain Neoplasms - metabolism / Brain Neoplasms - therapy / Cancer therapies / carrier‐free nanoparticles / Cell death / Cell Line, Tumor / Chlorophyllides / Copper - chemistry / cuproptosis / Cytotoxicity / Disease Models, Animal / Ferroptosis / Ferroptosis - drug effects / Fourier transforms / Glioblastoma - metabolism / Glioblastoma - therapy / Glioma / Humans / lipid peroxidation / Mice / Microscopy / Nanoparticles - chemistry / Porphyrins - chemistry / Porphyrins - pharmacology / Scientific imaging / sonodynamic therapy