A heme-regulatable chemodynamic nanodrug harnessing transcription factor Bach1 against lung cancer metastasis

Abstract Non-small cell lung cancer (NSCLC) is a type of cancer dominated by metastasis-induced death. The transcription factor BTB and CNC homology 1 (Bach1) regulates almost all metastasis steps by activating the transcription of critical metastatic genes. It is urgent to engineer a nanodrug enabling regulation of Bach1 against tumor metastasis. Herein, a minimalist nanodrug integrating chemodynamic therapy (CDT) and Bach1 degradation was reported to prevent metastasis of NSCLC. The nanodrug was achieved by self-assembly of ferrocene (Fc) and Tin protoporphyrin IX (TinPPIX). In our nanodrug, Fc not only triggers the production of highly cytotoxic ∙OH for tumor ablation via Fenton reaction, but also induces heme release from heme-containing proteins to stimulate Bach 1 degradation. Moreover, TinPPIX further augments the free heme level along with amplifies the CDT efficacy by disabling heme oxygenase-1 (HO-1)-mediated heme conversion into antioxidative bilirubin. The results showed that, compared with control group, TinPPIX/Fc nanodrug caused a four-fold increase in heme level, which triggered remarkable Bach1 degradation in Fbxo22-mediated manner and successfully inhibited Bach1-dominated metastasis. Therefore, this nanodrug could powerfully impeded NSCLC progression and metastasis, offering an innovative heme-regulatable chemodynamic therapeutic approach for lung cancer with strong metastasis capability.