Abstract

Intratumoral redox homeostasis is often implicated in the development of multidrug resistance (MDR), which compromises the oxidative cytotoxicity of anthracycline chemotherapeutics such as doxorubicin (DOX). To overcome the redox homeostasis-driven MDR, we analyzed the transcriptomes of 216 breast cancer patients, revealing a noteworthy association between the TRPA1 (a regulator of redox homeostasis) overexpression and drug resistance. Moreover, a smart magnetic nanozyme, HADAF (HA@Anti-TRPA1@DOX@Au@Fe3O4), was rationally designed to target TRPA1 and reverse MDR. HADAF nanozyme integrates Au@Fe3O4 nanosheets with DOX, antisense oligonucleotides of TRPA1 and hyaluronic acid (HA). Notably, the dynamic regulation of HADAF is triggered spatiotemporally by a controllable low-frequency vibrational magnetic field (VMF) and near-infrared (NIR) laser irradiation. In vitro and in vivo experiments showed that HADAF effectively inhibited the TRPA1/PI3K/mTOR/MCL-1 signaling pathway, promoting apoptosis and ferroptosis, and achieving a 90% inhibition rate in MCF-7/ADR cells. As a result of this engineered therapeutic approach, the combination therapy reduced the IC50 of DOX by 87.7-fold compared to free DOX. In summary, this multimodal nanozyme provides a novel strategy to target redox homeostasis and overcome MDR in cancer therapy.