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Iron accumulation and lipid peroxidation form the basis of ferroptosis, potentially circumventing the limitations of apoptosis in cancer treatment. Owing to the lack of potent ferroptosis inducers, the development of efficient ferroptosis-based therapeutic agents and protocols against cancers is highly challenging. Inspired by the topological effect of nanoparticles in modulating cellular function/status, a specific tetrapod ferroptosis-inducer iron-palladium (FePd) nanocrystal was rationally engineered for physically activated autophagy-augmented ferroptosis and enhanced cancer immunotherapy. Specifically, the tetrapod FePd nanocrystal featured strong peroxidase-/glutathione oxidase-mimicking bioactivities, which promoted cancer cell ferroptosis. The special spiky morphology and nanostructure of the FePd nanocrystal simultaneously induced autophagy, which augmented ferroptosis in cancer cells and triggered the release of inflammatory cytokines in macrophages for strengthening anti-PD-L1-antibody mediated immunotherapy, synergistically achieving the maximal antineoplastic effect in three tumor-bearing animal models. This unique physical activation strategy for efficient cancer treatment via precise morphological tuning represents a paradigm for nanomedicine design for efficient tumor treatment., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Science China Press. Published by Elsevier B.V. All rights reserved.)

The effective deployment of reactive oxygen species (ROS)-mediated oncotherapy in practice remains challenging, mired by uncontrollable catalytic processes, stern reaction conditions and safety concerns. Herein, we develop a copper nanodot integrating sonodynamic and catalytic effects within one active center, which responds to exogenous ultrasound (US) and endogenous H 2 O 2 stimuli. US irradiation induces the valence conversion from Cu II to Cu I catalyzing H 2 O 2 into ⋅OH for chemodynamic therapy. Meanwhile, valence transformation results in electron-hole pairs separation, promoting ROS generation for sonodynamic therapy. Notably, copper nanodots not only block lysosome fusion and degradation leading to autophagy flux blockage, but also interfere with the glutathione peroxidase 4 and cystine-glutamate antiporter SLC7A11 function achieving ferroptosis. Furthermore, reversible valence changes, inherent hydrophilicity and renal clearance ultrasmall size guarantee biosafety., (© 2022 Wiley-VCH GmbH.)

The effective deployment of reactive oxygen species (ROS)‐mediated oncotherapy in practice remains challenging, mired by uncontrollable catalytic processes, stern reaction conditions and safety concerns. Herein, we develop a copper nanodot integrating sonodynamic and catalytic effects within one active center, which responds to exogenous ultrasound (US) and endogenous H2O2 stimuli. US irradiation induces the valence conversion from CuII to CuI catalyzing H2O2 into ⋅OH for chemodynamic therapy. Meanwhile, valence transformation results in electron‐hole pairs separation, promoting ROS generation for sonodynamic therapy. Notably, copper nanodots not only block lysosome fusion and degradation leading to autophagy flux blockage, but also interfere with the glutathione peroxidase 4 and cystine‐glutamate antiporter SLC7A11 function achieving ferroptosis. Furthermore, reversible valence changes, inherent hydrophilicity and renal clearance ultrasmall size guarantee biosafety. [ABSTRACT FROM AUTHOR]

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 H2O2 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. [ABSTRACT FROM AUTHOR]

• The "mixed" types of cell death for treating therapy-resistant cancers were achieved by integrating sonodynamic therapy with ferroptosis-targeting based on the rationally constructed nanosonosensitizers. • Based on the conceptual advance of "targeting ferroptosis-sensitized sonodynamic tumor therapeutics", synergistic performance of multifunctional nanosonosensitizers in tumor suppression has been systematically demonstrated. • The biocompatibility and biosafety of this intriguing therapeutic nanosystem prospects the potential clinical translation based on its superb treatment outcomes. [Display omitted] Nanosensitizer-enabled sonodynamic therapy (SDT) represents an appealing anti-tumor modality to induce apoptotic cancer-cell death by generating highly toxic reactive oxygen species (ROS). However, it suffers from discounted therapeutic efficacy due to the apoptosis-resistant mechanism of cancer cells. Inspired by the synergistic anti-tumor effect of ferroptosis and apoptosis, in this work, we have constructed a nanosonosensitizer (PpIX)-based liposomal nanosystem, which simultaneously encapsulated clinically approved iron supplement ferumoxytol, for inducing dual ferroptosis/apoptosis pathways by SDT-based oxidative ferrotherapy. The ferumoxytol as a ferroptosis initiator is utilized to deliver excessive iron into cancer cells, which achieves tumor metabolic rewiring and renders cancer cells extremely susceptible to SDT-induced cell apoptosis. Meanwhile, SDT enables the modulation of critical regulatory ferroptosis checkpoints through the process of ferritinophagy so as to improve ferroptosis sensitivity, thus achieving synergistic tumor suppression. The potential benefits of triggering ferroptosis-like cell death in the context of sonodynamic cancer treatment were substantially evidenced by augmented therapeutic efficacy both in vitro and in vivo , suggesting that such an efficient SDT-based ferroptosis-targeting strategy is highly promising to be an innovative tumor-treatment approach. [ABSTRACT FROM AUTHOR]