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.
He et al. (Mon,) studied this question.