Ultrasound‐Augmented Nanocatalytic Ferroptosis Reverses Chemotherapeutic Resistance and Induces Synergistic Tumor Nanotherapy

Abstract Inducing ferroptosis has been acknowledged as an emerging strategy to kill drug‐resistant tumor cells, but how to efficiently induce ferroptosis at the tumor site and enhance its therapeutic efficacy are still highly challenging. In this work, an ultrasound (US)‐augmented nanocatalytic ferroptosis strategy is implemented by a GA‐Fe(II)‐based liposomal nanosystem, which simultaneously encapsulates doxorubicin hydrochloride (DOX), for reversing chemotherapeutic resistance and inducing synergistic ferroptosis/apoptosis‐based nanotherapy. GA‐Fe(II), as an iron‐containing Fenton catalyst that catalyzes the persistent conversion of H 2 O 2 to hydroxyl radicals, is utilized to deplete glutathione and deliver excess iron into cells for accumulating lipid peroxidation and inducing ferroptosis in DOX‐resistant MCF‐7/ADR cancer cells. US irradiation is capable of promoting cell phagocytosis of nano‐agents, enhancing Fenton reaction, and controlling drug release at tumor sites to strengthen nanocatalytic therapy. Transcriptomics analysis reveals that the US‐augmented Fenton reaction enables the down‐regulation of PGC‐1α and Bcl‐2 expression, rendering MCF‐7/ADR cells susceptible to DOX‐induced apoptosis. The distinct US‐responsive Fenton reaction collaborating with chemotherapy substantially reverses tumor drug resistance and achieves high tumor‐killing efficacy in MCF‐7/ADR cells and MCF‐7/ADR tumor‐bearing mice, suggesting that such a synergistic ferroptosis/apoptosis‐targeting strategy is instructive to the future design of therapeutic regimens against drug‐resistant tumors.