Inhalable Fibroin Hybrid Liposomes for the Targeted Treatment of Lung Adenocarcinoma via Autophagy-Enhanced Ferroptosis

作者：Lei Shu, Peili Luo, Chuanyu Ren, Ziwei Lai, Xuejuan Zhang, Chuanbin Wu, Xin Pan, Zhengwei Huang · 发表于：ACS Nano · 年份：2025 · DOI：10.1021/acsnano.5c09493 · 被引用次数：8 · 研究领域：Nanoplatforms for cancer theranostics、Extracellular vesicles in disease、Ferroptosis and cancer prognosis

The application of ferroptosis inducer FIN56 to decrease antioxidant levels in lung adenocarcinoma (LUAD) is a promising tumor eradication technique. However, several obstacles reduce the efficacy of ferroptosis therapy including insufficient oxidative stress from monotherapy and restricted drug retention in tumor tissues. To address these challenges, we developed an inhalable hybrid liposome in which FIN56 and piperlongumine (PPL) are coloaded into silk fibroin nanoparticles to overcome the limitation of the poor therapeutic effect of single-drug ferroptosis. Subsequently, lipids containing hyaluronic acid were added to the hybrid liposome to enable it to specifically target the overexpressed CD44 receptors on the surface of LUAD cells and solve the problem of insufficient active targeting of silk fibroin nanoparticles. Compared to conventional intravenous formulations, the as-synthesized formulation FP@SLCDH increased pulmonary accumulation by 13.6-fold and lipid peroxidation products by 2.14-fold. FIN56 prompts tumor-specific ferroptosis by inhibiting glutathione peroxidase 4 (GPX4) and glutathione (GSH), whereas PPL further augments this effect by increasing intracellular reactive oxygen species levels and facilitating ferritin degradation to release Fe ions from ferritin. The role of autophagy in promoting ferroptosis and therapeutic efficacy was validated in an orthotopic LUAD tumor model. The real-time tracking of targeted retention of FP@SLCDH in LUAD cells is also po...