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The emergence of chemotherapeutic resistance, which is closely related to the oxidative stress defense induced by the imbalance of reactive oxygen species (ROS), is one of the important reasons for the failure of anti-tumor therapy. Herein, a GSH-triggered ferroptosis/apoptosis integrated tumor therapy strategy was successfully implemented to prohibit the mitoxantrone (MTO) resistance. Owing to the overexpressed GSH in the tumor microenvironment, the tumor active targeting MTO-Cu(Ⅱ)-cRGD nanolocks could be dissociated to release Cu(Ⅰ) and MTO, which could persistently catalyze hydrogen peroxide into hydroxyl radicals (•OH) via Fenton-like reaction and generate photothermal effect, respectively. The depletion of GSH inactivated GPX4 for the accumulation of lipid peroxides (LPO) and inducing ferroptosis. With the destruction of oxidative stress defenses, the formation of chemotherapeutic resistance could be effectively prohibited. The nanolocks could eliminate the solid tumors through ferroptosis-sensitized chemotherapy under the guidance of photoacoustic imaging. The study proposed the mechanism of reversing chemotherapeutic resistance by ferroptosis, providing a feasible strategy for the treatment of drug-resistant tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Suffering from the laborious synthesis and undesirable tumor microenvironment response, the exploitation of novel NIR-II absorbing organic photothermal agents is of importance to promote phototherapeutic efficacy. Herein, two kinds of charge-transfer complex nanoparticles (TMB-F4TCNQ and TMB-TCNQ) are prepared by supramolecular assembly. Because of the larger energy gap between donor and acceptor, TMB-F4TCNQ presents higher charge-transfer degree (72 %) than that of TMB-TCNQ (48 %) in nanoaggregates. Therefore, TMB-F4TCNQ exhibits stronger NIR-II absorption ability with a mass extinction coefficient of 15.4 Lg -1  cm -1 at 1300 nm and excellent photothermal effect. Impressively, the specific cysteine response can make the TMB-F4TCNQ effectively inhibit the intracellular biosynthesis of GSH, leading to redox dsyhomeostasis and ROS-mediated ferroptosis. TMB-F4TCNQ can serve as a contrast agent for NIR-II photoacoustic imaging to guide precise and efficient photothermal therapy in vivo., (© 2021 Wiley-VCH GmbH.)

Suffering from the laborious synthesis and undesirable tumor microenvironment response, the exploitation of novel NIR‐II absorbing organic photothermal agents is of importance to promote phototherapeutic efficacy. Herein, two kinds of charge‐transfer complex nanoparticles (TMB‐F4TCNQ and TMB‐TCNQ) are prepared by supramolecular assembly. Because of the larger energy gap between donor and acceptor, TMB‐F4TCNQ presents higher charge‐transfer degree (72 %) than that of TMB‐TCNQ (48 %) in nanoaggregates. Therefore, TMB‐F4TCNQ exhibits stronger NIR‐II absorption ability with a mass extinction coefficient of 15.4 Lg−1 cm−1 at 1300 nm and excellent photothermal effect. Impressively, the specific cysteine response can make the TMB‐F4TCNQ effectively inhibit the intracellular biosynthesis of GSH, leading to redox dsyhomeostasis and ROS‐mediated ferroptosis. TMB‐F4TCNQ can serve as a contrast agent for NIR‐II photoacoustic imaging to guide precise and efficient photothermal therapy in vivo. [ABSTRACT FROM AUTHOR]