Lysosome-hijacking inhalable nanomimosa enhances ferroptosis for lung cancer therapy

Ferroptosis therapy shows potential for lung tumor treatment, but precise accumulation of reactive oxygen species (ROS) remains a challenge. A lysosome-hijacking strategy was developed, aiming to induce ROS spread from lysosomes to the entire cell. The key is delivering a ROS inducer to the lysosome for rapid and targeted ROS generation. In this study, transferrin (Tf) was anchored on nanomicelles to create Tf-Mic, with a coordination effect between surface carboxyl groups and Fe³⁺. The Fenton-like reaction substrate dihydroartemisinin (DHA) and system Xc- (xCT) inhibitor sorafenib (SRF) were encapsulated to form inhalable Tf-Mic@SD, or "nanomimosa," which undergoes a conformation transition in response to stimuli. Upon inhalation, nanomimosa is captured by tumor cells through transferrin receptor (TfR) recognition, then endocytosed by lysosomes, where Tf undergoes a conformational change. This releases Fe³⁺, DHA, and SRF, causing a rapid generation of ROS. The ROS amplification accelerates ferroptosis, leading to faster tumor elimination both in vitro and in vivo. This study provides a versatile approach using lysosome-hijacking to enhance ferroptosis therapy for cancer treatment.