Issue 2, 2022

A self-amplifying nanodrug to manipulate the Janus-faced nature of ferroptosis for tumor therapy

Abstract

Ferroptosis, an unusual non-apoptotic cell death caused by the iron-dependent accumulation of lipid peroxide, enables the flexible design of an antitumor platform. Specifically, as a positive role, ferroptosis can induce an immune response accompanied with the interferon-γ (IFN-γ)-triggered disruption of the glutathione peroxidase 4 pathway for cascade enhancement of ferroptotic cell death and ferroptosis-induced immunotherapeutic efficacy. However, as a negative role, ferroptosis also triggers inflammation-associated immunosuppression by up-regulation of the cyclooxygenase-2/prostaglandin E2 pathway and IFN-γ-associated adaptive immune resistance by up-regulation of programmed death ligand-1 (PD-L1), impeding the antitumor efficacy of multiple immune cells by immune escape. Negative and positive roles endow ferroptosis with a Janus-faced nature. It is urgent to manipulate the Janus-faced nature of ferroptosis for eliciting the maximized ferroptotic therapeutic efficacy. Herein, a self-amplifying nanodrug (RCH NPs) was designed by co-assembling hemin (ferric porphyrin), celecoxib (anti-inflammatory drug) and roscovitine (cyclin-dependent kinase 5 inhibitor) with the assistance of human serum albumin for reprograming the Janus-faced nature of ferroptosis. During hemin-triggered ferroptosis, celecoxib disrupted the inflammation-related immunosuppression while roscovitine destroyed the IFN-γ-induced up-regulation of PD-L1 via the genetic blockade effect. The RCH NPs thus demonstrated superior therapeutic effects on tumors, thanks to self-amplifying ferroptotic immunotherapy. Our work offers a conceptually innovative strategy for harnessing ferroptosis against tumors.

Graphical abstract: A self-amplifying nanodrug to manipulate the Janus-faced nature of ferroptosis for tumor therapy

Supplementary files

Article information

Article type
Communication
Submitted
24 Sept. 2021
Accepted
21 Dec. 2021
First published
21 Dec. 2021

Nanoscale Horiz., 2022,7, 198-210

A self-amplifying nanodrug to manipulate the Janus-faced nature of ferroptosis for tumor therapy

M. Zhang, X. Qin, Z. Zhao, Q. Du, Q. Li, Y. Jiang and Y. Luan, Nanoscale Horiz., 2022, 7, 198 DOI: 10.1039/D1NH00506E

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