Glutathione Depletion‐Induced Activation of Dimersomes for Potentiating the Ferroptosis and Immunotherapy of “Cold” Tumor

Abstract

The abundant glutathione (GSH) in “cold” tumors weakens ferroptosis therapy and the immune response. Inspired by lipids, we fabricated cinnamaldehyde dimers (CDC) into lipid‐like materials to form dimersomes capable of depleting GSH and delivering therapeutics to potentiate the ferroptosis and immunotherapy of breast cancer. The dimersomes exhibited superior storage stability for over one year. After reaching the tumor, they quickly underwent breakage in the cytosol owing to the conjugation of hydrophilic GSH on CDC by Michael addition, which not only triggered the drug release and fluorescence switch “ON”, but also led to the depletion of intracellular GSH. Ferroptosis was significantly enhanced after combination with sorafenib (SRF) and elicited a robust immune response in vivo by promoting the maturation of dendritic cells and the priming of CD8+ T cells. As a result, the CDC@SRF dimersomes cured breast cancer in all the mice after four doses of administration.

Cold Nanozyme for Precise Enzymatic Antitumor Immunity

“…Obviously, compared to cells in the blank group, Bi 2 Fe 4 O 9 NSs with cold temperature downregulated the expression of GPX4 by 98% (Figure D,E). GPX4 has been well demonstrated as a critical regulator of cell ferroptosis, , which is characterized with lipid peroxidation. , To confirm the involvement of ferroptosis, lipid oxidation was detected using C11-BODIPY as a fluorescent probe . Due to the lipophilicity, C11-BODIPY with red fluorescence was prone to insert into the plasma membrane.…”

Targeting ferroptosis, the achilles’ heel of breast cancer: A review

“…PCBMA promoted the accumulation of Fe3O4@PCBMA in tumor lesions, while SIM inhibited the expression of HMGCR, thereby downregulating mevalonate pathway and GPX4 expression, and inducing ferroptosis ( Yao et al, 2021 ). Cinnamaldehyde dimers (CDCs) induce lipid materials to form dimers, which enable them to deplete GSH and deliver therapeutics to enhance ferroptosis and immunotherapeutic effects against breast cancer ( Zhou Z. et al, 2022 ). The nanoparticles consisting of ferritin and a pH-sensitive molecular switch (FPBC@SN) disintegrate in the acidic cytoplasm and release sorafenib and an indoleamine2,3-dioxygenase (IDO) inhibitor NLG919.…”

Recent Advances of Fluorescence Probes for Imaging of Ferroptosis Process

“…Ferroptosis is executed by the accumulation of lipid peroxides to lethal levels. In ferroptosis, the lipid peroxidation of polyunsaturated fatty acids can be induced by two different pathways [11,12]: one is blocking cystine uptake of the cystine/glutamate antiporter system x c − on cell membrane by ferroptosis inducer such as erastin, to deplete intracellular biothiols, including cysteine (Cys) and its downstream product glutathione (GSH), and finally cause the inactivation of the main lipid peroxides eliminator glutathione peroxidase 4 (GPX4) [1,13,14]; the other one is the covalent inactivation of GPX4 by some specific GPX4 inhibitors (e.g., RSL3) [15]. It is clear that iron, reactive oxygen species (ROS) and biothiols play crucial and highly related roles in the development and redox regulation in ferroptosis (Figure 1).…”