Fibroin nanodisruptor with Ferroptosis-Autophagy synergism is potent for lung cancer treatment

Chemotherapy agents for lung Cancer often cause apoptotic resistance in cells, leading to suboptimal therapeutic outcomes. FIN56 can be a potential treatment for lung Cancer as it induces non-apoptotic cell death, namely Ferroptosis. However, a bottleneck exists in FIN56-induced Ferroptosis treatment; specifically, FIN56 fails to induce sufficient oxidative stress and may even trigger the defense system against Ferroptosis, resulting in poor therapeutic efficacy. To overcome this, this study proposed a strategy of co-delivering FIN56 and piperlongumine to enhance the Ferroptosis treatment effect by increasing oxidative stress and connecting with the Autophagy pathway. FIN56 and piperlongumine were encapsulated into silk fibroin-based nano-disruptors, named FP@SFN. Characterization results showed that the particle size of FP@SFN was in the nanometer range and the distribution was uniform. Both in vivo and in vitro studies demonstrated that FP@SFN could effectively eliminate A549 cells and inhibit subcutaneous lung Cancer tumors. Notably, Ferroptosis and Autophagy were identified as the main cell death pathways through which the nano-disruptors increased oxidative stress and facilitated cell membrane rupture. In conclusion, nano-disruptors can effectively enhance the therapeutic effect of Ferroptosis treatment for lung Cancer through the ferroptosis-autophagy synergy mechanism, providing a reference for the development of related therapeutics.

Autophagy; FIN56; Ferroptosis; Lung cancer; Nanodisruptor; Piperlongumine.