Nanodrugs Manipulating Endoplasmic Reticulum Stress for Highly Effective Antitumor Therapy

Abstract

Cancer is one of the leading causes of death worldwide due to high morbidity and mortality. Many attempts and efforts have been devoted to fighting cancer. Owing to the significant role of the endoplasmic reticulum (ER) in cell function, inducing ER stress can be promising for cancer treatment. However, the sustained activation of cytoprotective unfolded protein response (UPR) presents a tremendous obstacle for drugs in inducing unsolved ER stress in tumor cells, especially small-molecule drugs with poor bioavailability. Therefore, many emerging nanodrugs inducing and amplifying ER stress have been developed for efficient cancer treatment. More importantly, the novel discovery of ER stress in immunogenic cell death (ICD) makes it possible to repurpose antitumor drugs for immunotherapy through nanodrug-based strategies amplifying ER stress. Therefore, this mini-review aims to provide a comprehensive summary of the latest developments of the strategies underlying nanodrugs in the treatment of cancer via manipulating ER stress. Meanwhile, the prospects of ER stress–inducing nanodrugs for cancer treatment are systematically discussed, which provide a sound platform for novel therapeutic insights and inspiration for the design of nanodrugs in treating cancer.

Epigallocatechin-3-gallate Mo nanoparticles (EGM NPs) efficiently treat liver injury by strongly reducing oxidative stress, inflammation and endoplasmic reticulum stress

“…Intracellular ROS, which disrupt ER function, induce ER stress based on the accumulation of unfolded and misfolded proteins in the ER. Unfolded and misfolded proteins in the ER lead to the release of Bip and activation of ER transmembrane protein (IRE1α, PERK and ATF6) (Xiang et al, 2022). The phosphorylated IRE1α will covert e unspliced XBP1 protein (uXBP1) to the highly active sXBP1.…”

Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic‐Reticulum‐Targeted Therapy: Left or Right?

“…Endoplasmic reticulum (ER) is a vital organelle responsible for protein folding, intracellular homeostasis regulation, and cell proliferation in eukaryotic cells, which establishes ER as a potentially effective target for anticancer therapy. [ 1 , 2 , 3 ] In a previous study, we synthesized a library of doxorubicin (DOX) derivatives with various targeting subunits, including small molecules and short peptides, redirecting the intracellular fate of DOX from nucleus to ER. Our study found that the ER‐targeting efficiency of DOX positively correlated with the capability to induce immunogenic cell death (ICD).…”