Open pocket and tighten holes: Inhalable lung cancer-targeted nanocomposite for enhanced ferroptosis-apoptosis synergetic therapy

Cisplatin (DDP)-based ferroptosis-apoptosis synergetic therapy is a novel strategy of lung cancer treatment based on the targeted induction of high oxidative stress levels in tumor cells. Nevertheless, the strong antioxidant system in tumor cells and low accumulation at the lesion site result in its low sensitivity as well as systemic side effects. To circumvent the strong antioxidant system, the combination of Reactive Oxygen Species (ROS) generator DDP and a glutathione (GSH) scavenger β-Phenethyl isothiocyanate (PEITC) was a potential strategy. Besides, pulmonary delivery equipped with lung tumor targeting nanoformulations was expected to promote tumor lesions accumulation. Herein, an inhalable core–shell nanocomposite, PEITC-loaded solid lipid nanocores coated with DDP-encapsulated hyaluronic acid (HA) shell (PNDH) based on the strategy of “open pocket and tighten holes” was developed. The nicotinamide adenine dinucleotide phosphate oxidases 4 (NOX4) was upregulated by DDP to “open pocket for ROS” while the PEITC could deplete the GSH to “tighten holes”, preventing ROS consumption. Upon nebulization, improved lung drug accumulation with about 6.7 times higher than intravenous injection and excellent lung retention was exhibited. Equipped with tumor membrane CD44 targeted HA, the tumor recognizing efficiency was elevated about two times. The remarkably enhanced tumor inhibition effect was revealed both in vitro and in vivo, and the PNDH-driven cell damage process was described as a result of mitochondrial dysfunction and osmotic pressure mediated cell membrane broken. Taken together, the rationally designed PNDH enhanced the effectiveness of ferroptosis-apoptosis synergetic therapy by the “open pocket and tighten holes” strategy.