Smart Magnetic Nanozyme for Multimodal Dynamic Regulation to Reverse Multidrug Resistance in Breast Cancer.

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 (a regulator of redox homeostasis) overexpression and drug resistance. Moreover, a smart magnetic nanozyme, HADAF (HA@Anti-@DOX@Au@FeO), was rationally designed to target and reverse MDR. HADAF nanozyme integrates Au@FeO nanosheets with DOX, antisense oligonucleotides of 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 /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 IC 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.