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.