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Reactive X species (RXS), encompassing elements such as O, N, C, S, Se, Cl, Br, I, and H, play vital roles in cell biology and physiological function, impacting cellular signal transduction, metabolic regulation, and disease processes. The redox unbalance of RXS is firmly implicated in an assortment of physiological and pathological disorders, including cancer, diabetes, cardiovascular disease, and neurodegenerative diseases. However, the intricate nature and multifactorial dependence of RXS pose challenges in comprehending and precisely modulating their biological behavior. Nanomaterials with distinct characteristics and biofunctions offer promising avenues for generating or scavenging RXS to maintain redox homeostasis and advance disease therapy. This minireview provides a tutorial summary of the relevant chemistry and specific mechanisms governing different RXS, focusing on cellular metabolic regulation, stress responses, and the role of nanomedicine in RXS generation and elimination. The challenges associated with chemically regulating RXS for diverse disease treatments are further discussed along with the future prospects, aiming to facilitate the clinical translation of RXS-based nanomedicine and open new avenues for improved therapeutic interventions., (© 2023 Wiley-VCH GmbH.)

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) has gradually come into the limelight for oncological treatment due to its noninvasiveness, high specificity, and low side effects. However, upregulated heat-shock proteins (HSPs) and reactive oxygen species (ROS)-defensing system such as glutathione (GSH) or MutT homolog 1 (MTH1) protein in tumor microenvironment counteract the efficiency of single-modality therapy either PTT or PDT. Herein, the well-defined bismuth telluride nanoplates (Bi 2 Te 3 NPs) are engineered with a high-performance photo-thermo-electro-catalytic effect for tumor-synergistic treatment. Upon near-infrared light illumination, Bi 2 Te 3 NPs induce a significant temperature elevation for PTT, which effectively inhibits MTH1 expression. Especially, heating and cooling alteration caused temperature variations result in electron-hole separation for ROS generation, which not only damages HSPs to reduce the thermotolerance for enhance PTT, but also arouses tumor cell pyroptosis. Additionally, Bi 2 Te 3 NPs conspicuously reduce GSH, further improving ROS level and leading to decrease glutathione peroxidase 4 (GPX4) activity, which triggers tumor cell ferroptosis. Due to the photo-thermo-electro-catalytic synergistic therapy, Bi 2 Te 3 NPs are gifted with impressive tumor suppression on both ectopic and orthotopic ocular tumor models. This work highlights a high-performance multifunctional energy-conversion nanoplatform for reshaping tumor microenvironment to boost the tumor-therapeutic efficacy of phototherapy., (© 2023 Wiley-VCH GmbH.)

The development of covalent organic framework (COF) sonosensitizers with intrinsic sonodynamic effects is highly desirable. However, such COFs are generally constructed using small-molecule photosensitizers. Herein, we report that the reticular chemistry-based synthesis of COFs from two inert monomers yields a COF-based sonosensitizer (TPE-NN) with inherent sonodynamic activity. Subsequently, a nanoscale COF TPE-NN is fabricated and embedded with copper (Cu)-coordinated sites to obtain TPE-NN-Cu. Results show that Cu coordination can enhance the sonodynamic effect of TPE-NN, whereas ultrasound (US) irradiation for sonodynamic therapy can augment the chemodynamic efficacy of TPE-NN-Cu. Consequently, TPE-NN-Cu upon US irradiation shows high-performance anticancer effects based on mutually reinforced sono-/chemo-nanodynamic therapy. This study reveals the backbone-originated sonodynamic activity of COFs and proposes a paradigm of intrinsic COF sonosensitizers for nanodynamic therapy., (© 2023 Wiley-VCH GmbH.)

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 anticancer mechanism of nanozymes is dominantly associated with the capacity for generation of reactive oxygen species (ROS) caused by the valence change of metal elements. However, very little research is focused on and has achieved the exploration and development of enzyme-mimicking activities of valence-invariable metal compounds. Herein, a distinct valence-invariable calcium fluoride (CaF 2 ) nanozyme with ultrasound (US)-enhanced peroxidase (POD)-mimicking activity is rationally designed and engineered for efficient calcium (Ca 2+ )-overload-enhanced catalytic tumor nanotherapy, which is the first paradigm of Ca-based nanozymes for catalytic cancer treatment. The release of exogenous Ca 2+ ions from CaF 2 nanocrystals and deleterious ROS generation derived from US-amplified POD-mimicking properties facilitate intracellular Ca 2+ accumulation and achieve Ca 2+ -overload-induced mitochondrial dysfunction through introducing exogenous Ca 2+ ions and regulating calcium-pumping channels of neoplastic cells. Especially, US as an exogenous energy input is capable of substantially amplifying POD-mimicking catalytic activities of CaF 2 nanozyme, ultimately achieving efficient anti-neoplastic outcome on both 4T1 breast tumor and H22 hepatic carcinoma animal models. Such a discovery of enzyme-like activity of valence-invariable metal compounds can broaden the cognition scope of nanozymes and effectively serves the field of catalytic and chemoreactive nanomedicine., (© 2022 Wiley-VCH GmbH.)

Background: Sonodynamic therapy (SDT) is a burgeoning modality for cancer therapy owing to its high tissue-penetrating capability, controllability and safety. Whereas, the undesirable reactive oxygen species (ROS) yield of sonosensitizers and tumor hypoxia are two vulnerable spots of SDT. Therefore, it is an advisable strategy to augment ROS level and simultaneously relieve hypoxia for SDT to arrive its full potential in cancer treatment., Results: In this work, the defected two-dimensional (2D) Pd/H-TiO 2 nanosheets (NSs) with triple antineoplastic properties were dexterously elaborated and engineered using a facile one-pot Pd-catalyzed hydrogenation tactic by loading a tiny amount of Pd and then inletting hydrogen flow at atmospheric pressure and temperature. The 2D black Pd/H-TiO 2 NSs with oxygen defects exerted eximious SDT effect based on the decreased bandgap that made it easier for the separation of electrons and holes when triggered by ultrasound as theoretically guided by density functional theory calculations. Additionally, Pd/H-TiO 2 NSs could serve as Fenton-like agents because of the presence of oxygen defects, facilitating the conversion of hydrogen peroxide into hydroxyl radicals for exerting the chemodynamic therapy (CDT). Simultaneously, the introduced tiny Pd component possessed catalase-like activity responsible for oxygen production to ameliorate hypoxic condition and thus contributed to improving SDT and CDT efficacies. Both in vitro and in vivo results provided compelling evidences of high ROS yield and aggrandized sono-chemodynamic effect of Pd/H-TiO 2 nanosonosensitizers with the detailed underlying mechanism investigation by RNA sequencing., Conclusion: This work delves the profound potential of Pd-catalyzed hydrogenated TiO 2 on oncotherapy, and the effective antineoplastic performance and ignorable therapeutic toxicity make it a powerful competitor among a cornucopia of nanosonosensitizers., (© 2022. The Author(s).)

Photothermal therapy (PTT) has emerged as a distinct therapeutic modality owing to its noninvasiveness and spatiotemporal selectivity. However, heat-shock proteins (HSPs) endow tumor cells with resistance to heat-induced apoptosis, severely lowering the therapeutic efficacy of PTT. Here, a high-performance pyroelectric nanocatalyst, Bi 13 S 18 I 2 nanorods (NRs), with prominent pyroelectric conversion and photothermal conversion performance for augmented pyrocatalytic tumor nanotherapy, is developed. Canonical binary compounds are reconstructed by inserting a third biocompatible agent, thus facilitating the formation of Bi 13 S 18 I 2 NRs with enhanced pyrocatalytic conversion efficiency. Under 808 nm laser irradiation, Bi 13 S 18 I 2 NRs induce a conspicuous temperature elevation for photonic hyperthermia. In particular, Bi 13 S 18 I 2 NRs harvest pyrocatalytic energy from the heating and cooling alterations to produce abundant reactive oxygen species, which results in the depletion of HSPs and hence the reduction of thermoresistance of tumor cells, thereby significantly augmenting the therapeutic efficacy of photothermal tumor hyperthermia. By synergizing the pyroelectric dynamic therapy with PTT, tumor suppression with a significant tumor inhibition rate of 97.2% is achieved after intravenous administration of Bi 13 S 18 I 2 NRs and subsequent exposure to an 808 nm laser. This work opens an avenue for the design of high-performance pyroelectric nanocatalysts by reconstructing canonical binary compounds for therapeutic applications in biocatalytic nanomedicine., (© 2021 Wiley-VCH GmbH.)

Hypoxia can increase the resistance of tumor cells to radiotherapy and chemotherapy. However, the dense extracellular matrix, high interstitial fluid pressure, and irregular blood supply often serve as physical barriers to inhibit penetration of drugs or nanodrugs across tumor blood microvessels into hypoxic regions. Therefore, it is of great significance and highly desirable to improve the efficiency of hypoxia-targeted therapy. In this work, living photosynthetic bacteria (PSB) are utilized as hypoxia-targeted carriers for hypoxic tumor therapy due to their near-infrared (NIR) chemotaxis and their physiological characteristics as facultative aerobes. More interestingly, we discovered that PSB can serve as a kind of photothermal agent to generate heat through nonradiative relaxation pathways due to their strong photoabsorption in the NIR region. Therefore, PSB integrate the properties of hypoxia targeting and photothermal therapeutic agents in an "all-in-one" manner, and no postmodification is needed to achieve hypoxia-targeted cancer therapy. Moreover, as natural bacteria, noncytotoxic PSB were found to enhance immune response that induced the infiltration of cytotoxicity T lymphocyte. Our results indicate PSB specifically accumulate in hypoxic tumor regions, and they show a high efficiency in the elimination of cancer cells. This proof of concept may provide a smart therapeutic system in the field of hypoxia-targeted photothermal therapeutic platforms.