Chondroitin sulfate nanoparticles based on co-delivery dual drug induced ferroptosis in lung cancer cells by disrupting mitochondrial oxidative homeostasis
He Wang, Shuimu Lin, Jiacui Xie, Xuming Chen, Yating Deng, Pei Huang, Kanglong Peng, Wenhui Gao, Guodong Ye, Guihua Wang, Xiyong Yu, Huaying Wen, Linghao Qin, Yi Zhou
Abstract
Mitochondrial REDOX homeostasis is unbalanced by large amounts of reactive oxygen species production and reduced glutathione, leading to lipid oxidation-induced ferroptosis, which enhanced cancer immunotherapy. Thus, disrupting mitochondrial redox homeostasis represents a promising strategy for the treatment of lung cancer. In this study, a co-delivery system of based on chondroitin sulfate (CS) (CS-CA-CUR-TPP, CCCT) for natural medicines (Curcumin, CUR; and Cinnamaldehyde CA) was successfully constructed, which resulted in elevated ROS levels in cancer cells. Under the action of CS specifically targeting tumor cells, CCCT NPs is enriched and taken up by lung cancer cells. Acid responsiveness causes the CCCT NPs to break and escape from the lysosome, and CUR targets and destroys mitochondria under the action of mitochondrial target head triphenylphosphine (TPP). CA collaborates with CUR to produce large amounts of ROS and reduce GSH in a time-dependent manner in mitochondria for disruption of REDOX homeostasis, and triggers ferroptosis by reducing the expression of GXP4 and xCT proteins. The immunogenic cell death (ICD) after ferroptosis promotes interferon γ (IFN-γ), TNF-a, and IL-6 secretion. Our results desmontrat CCCT can promote inhibition of tumor growth by enhancing tumor immunogenicity. This study may provide a potential avenue for the advancement of self-delivery nanoparticles to overcome resistance to apoptosis in tumor therapy. • The dual-drug delivery nanoparticles (CCCT) based on chondroitin sulfate not only inhibit the proliferation of lung cancer cells, but also have high biosafe. • The combination of CA and CUR derived from Traditional Chinese Medicine can synergistically inhibit tumor cells proliferation, thereby addressing the issue of limited efficacy observed with individual administration. • By disrupting REDOX homeostasis, CCCT NPs induce lipid oxidation, promotes ferroptosis, enhance cancer immunotherapy, and overcome apoptosis tolerance. The results further elucidate the time - and dose-dependent effect of CCCT on lung cancer by acting on mitochondria rather than cytoplasm. • The integration of stepwise targeting and dual-response technology makes CCCT NPs smarter and improves their potential for tumor treatment.