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Nanomedicine‐induced cancer cell death has become a prominent area of research in the life sciences field in recent years. The concept of cuproptosis was first proposed in 2022. Copper homeostasis in organisms is tightly regulated by protein transporters and molecular chaperones. Disruptions in copper homeostasis can adversely affect mitochondrial respiration and disrupt other physiological processes, leading to cytotoxicity. Therefore, researchers have designed and refined copper‐based nanomaterials to induce cuproptosis and assess their effects on cancer treatment. While several reviews on cuproptosis exist, they primarily delve into its molecular mechanisms. This review begins with elucidating the metabolism and homeostasis of copper in the body. Subsequently, the latest advancements in copper nanomaterial‐induced cuproptosis for cancer treatment and antimicrobial purposes is summarized. Finally, a comprehensive summary and outlook on the subject is provided. The goal with this review is to assist researchers in gaining a deeper understanding of the interaction between nanomaterials and cuproptosis, thereby offering new perspectives for designing novel nanomaterials to induce cuproptosis.

Abstract One of the most important issues in the design and preparation of drug delivery systems in the recent years is versatility which includes providing synergistic therapeutic effects and sustainability. This study uses a redox‐active ferrocenyl surfactant (FcN+(CH2CH3)3(CH2)10CH3, Fc(C11) where Fc is ferrocene) and pH responsive Zeolitic Imidazolate Framework‐8 (ZIF‐8) structures to form multifunctional assemblies (Fc(C11)‐AOT/Rhb@ZIF‐8/PDA) that can be used in several application including the drug delivery. The vesicles prepared using AOT‐FC(C11) constitute the core of the structure. Since the location of the ferrocene group in the molecule structure, which is next to head group, the surface of the vesicles is decorated with the ferrocene group which can act as a Fenton reaction catalyst. The polydopamine (PDA) covered ZIF‐8 are used to decorate the surface of the vesicles, creating a truly remarkable structure. The porous structure of ZIF‐8 as well as the core of the vesicles can accommodate drug molecules. With the added NIR‐responsive character upon PDA coating, this assembled structure can be used for phototermal therapy applications. The properties of this designed multifunctional and multi‐responsive system are studied at different pH and under NIR‐laser irradiation and show that it has potential to display a triple chemodynamic/ photothermal/ chemotherapeutic effect.

Transdermal drug delivery system (TDDS) offers lower systemic toxicity and good patient compliance, making it a promising treatment option for skin-related cancers. However, physiological barriers in the skin frequently impede the therapeutic efficiency of TDDS. To address this, a unique self-assembled TDDS that incorporates disulfide pendant groups (termed Sup-TDDS) is presented. It is formulated with dithiolane-containing lipoic acid (LA), photosensitizers Ce6, and chemotherapeutic agents trametinib. Pendant disulfide moieties on Sup-TDDS facilitate thiol-disulfide exchange reactions with exofacial thiols on cell surfaces, thus enhancing stratum corneum penetration. In contrast to intravenous injection, topical administration of Sup-TDDS can penetrate deeper into the skin (> 500 µm) and promote drug accumulation in subcutaneous tumors. In a B16F10-bearing mouse model, Sup-TDDS treatment demonstrates significant anti-tumor effects in primary and recurrent melanoma, benefiting from the synergistic effects of Ce6 and trametinib. These results underscore that Sup-TDDS's transdermal properties allow non-invasive melanoma therapy, implying the potential of nanodrugs containing pendant disulfides for transdermal treatment of skin illnesses., (© 2024 Wiley‐VCH GmbH.)

Malignant tumor has become one of the hellish killers threatening the health of people around the world, its diagnosis and treatment has become the concerns of public. However, the optimal therapeutic dose, undesired side-effect, and long-term immune activation were key and bottleneck problems in tumor treatment. Herein, different batches of supramolecular therapeutic platforms, including vesicles, spherical nanoparticles, and cylindrical nanorods, with precise ratios of dye to drug (1:2) and multiple stimulus responsiveness were constructed by host-guest complexation between cyanine-camptothecin conjugates (IR780-CPT2) and β-cyclodextrin (β-CD) pendent hydrophilic copolymers. The reduction responsiveness, near-infrared photothermal conversion and singlet oxygen ( 1 O 2 ) generation performances endowed these platforms excellent cancer cells killing effect in both of in vitro cellular experiments and in vivo mice models. More importantly, without affecting the weight of mice, the maturation of dendritic cells, proliferation of T cells, up-regulation of high mobility group protein B1, and reduction of immunosuppressive regulatory T cells were detected after employing a synergistic chemo-photo therapy, demonstrating the body's immune effect was successfully activated. Thus, during the treatment of primary tumor, the distal tumor was also inhibited. We believe this work could provide a distinctive way to fabricate supramolecular theranostic platforms with different morphologies and improve antitumor and antimetastasis capabilities., (© 2024 Wiley‐VCH GmbH.)

In wound healing and clinical anti-infection therapy, the current feasibility of nanocatalysts is extremely limited because of inadequate reactive oxygen species (ROS) generation. Herein, a novel H 2 O 2 self-supplying nanocomposite (M/C/AEK) consists of molybdenum disulfide (MoS 2 ) decorated with calcium peroxide (CaO 2 ) prepared at ambient temperature and encapsulated in AEK hydrogel. In the presence of H 2 O 2 and poly(vinyl pyrrolidone) (PVP), CaO 2 nanoclusters, ≈30 nm, are anchored on the MoS 2 surface. MoS 2 /CaO 2 can induce both a cascaded peroxidase (POD)-like and catalase (CAT)-like catalytic activity to produce toxic hydroxyl radicals through self-supplied H 2 O 2 and O 2 responsive to the faintly acidic environment of acute wounds. The POD-like activity is increased under acidic compared with neutral conditions, allowing selective treatment of acute, slightly acidic wounds while avoiding the side effects of high-concentration antibacterial agents on normal tissues. The high near-infrared photothermal effect synergistically with POD-like/CAT-like activity of MoS 2 /CaO 2 boosts the production of more ROS to eradicate Staphylococcus aureus and Escherichia coli bacteria (98.6% and 98.9%) effectively and selectively stimulate wound healing. The porous M/C/AEK hydrogel in the wound microenvironment can efficiently capture bacteria, and its Ca 2+ ions and keratin stimulate healing, revealing excellent potential in advanced wound care and infection control therapies., (© 2024 Wiley‐VCH GmbH.)

Arsenic agents have shown great potential in fighting leukemia, but are poorly known in treating solid tumors, mainly ascribing to the rapid clearance and low targeting ability. It is reported that morphology modulation can enhance the interaction between nanoparticles and cell membrane. Herein, a dismountable protein corona-modified virus-like manganese-arsenic nanomedicine (vMnAs@HR) is rationally proposed for realizing safe and targeted delivery and synergistic arsenotherapy. The virus-like manganese-arsenic nanoparticle (vMnAs) is constructed followed by modification of a temporary R848-loaded HDL (HR) protein corona. Upon intravenous injection, the HR protein corona is stable and actively targeted to tumor tissue by taking advantage of the interaction between HDL and its receptor SR-BI. Intriguingly, upon accumulated in the tumor, HR can be jettisoned and interacted with macrophages for proinflammatory phenotype modulation. The re-exposed vMnAs can efficiently enhance endocytosis by taking advantage of the rationally designed spiky morphology. Moreover, the released double-stranded DNA (dsDNA) and manganese ions during tumor cell apoptosis can cooperatively activate cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway of DCs for systematic immune activation. It is anticipated that this morphology-transformable nanomedicine can realize safe and efficient arsenic delivery for synergistic arsenotherapy., (© 2024 Wiley‐VCH GmbH.)

Reactive oxygen species (ROS)-mediated emerging treatments exhibit unique advantages in cancer therapy in recent years. While the efficacy of ROS-involved tumor therapy is greatly restricted by complex tumor microenvironment (TME). Herein, a dual-metal CaO 2 @CDs-Fe (CCF) nanosphere, with TME response and regulation capabilities, are proposed to improve ROS lethal power by a multiple cascade synergistic therapeutic strategy with domino effect. In response to weak acidic TME, CCF will decompose, accompanied with intracellular Ca 2+ upregulated and abundant H 2 O 2 and O 2 produced to reverse antitherapeutic TME. Then the exposed CF cores can act as both Fenton agent and sonosensitizer to generate excessive ROS in the regulated TME for enhanced synergistic CDT/SDT. In combination with calcium overloading, the augmented ROS induced oxidative stress will cause more severe mitochondrial damage and cellular apoptosis. Furthermore, CCF can also reduce GPX4 expression and enlarge the lipid peroxidation, causing ferroptosis and apoptosis in parallel. These signals of damage will finally initiate damage-associated molecular patterns to activate immune response and to realize excellent antitumor effect. This outstanding domino ROS/calcium loading synergistic effect endows CCF with excellent anticancer effect to efficiently eliminate tumor by apoptosis/ferroptosis/ICD both in vitro and in vivo., (© 2024 Wiley‐VCH GmbH.)

Developing synergistic targeted therapeutics to improve treatment efficacy while reducing side effects has proven promising for anticancer therapies, but how to conveniently modulate multidrug cooperation remains a challenge. Here, a novel synergistic strategy using a G-quadruplex-programmed versatile nanorobot (G4VN) containing two subunits of DNAzyme (DzG4) and ligand-drug conjugates (LDCs) is proposed to precisely target tumors and then execute both gene silencing and chemotherapy. As the core module of this nanorobot, a well-designed G4 responding to a high level of K + in tumor microenvironment smartly kills three birds with one stone, which makes two TfR aptamers proximate to improve their efficiency of targeting tumor cells, and in situ activates a split 10-23 DNAzyme to downregulate target mRNA expression, meanwhile promotes the cell uptake of a GSH-responsive LDCs to enhance drug efficacy. Such a design enables a potently synergistic anticancer therapy with low side effects in vivo, showing great promise for broad applications in precision disease treatment., (© 2024 Wiley‐VCH GmbH.)

Cancer cells support their uncontrolled proliferation primarily by regulating energy metabolism. Inhibiting tumor growth by blocking the supply of nutrients is an effective treatment strategy. Fasting-mimicking diet (FMD), as a low-calorie, low-protein, low-sugar, high-fat diet, can effectively reduce the nutrient supply to tumor cells. However, the significant biological barrier presented by the tumor microenvironment imposes greater demands and challenges for drug design. This study constructs the multifunctional nanocomposite ZnFe 2 O 4 @TiO 2 @CHC@Orl-FA (ZTCOF), which has great potential to overcome the aforementioned drawbacks. ZnFe 2 O 4 @TiO 2 could produce 1 O 2 with ultrasound, and stimulate the Fenton-like conversion of endogenous H 2 O 2 to ·OH, achieving a combined therapeutic effect of sonodynamic therapy (SDT) and chemodynamic therapy (CDT). Orl (Orlistat) and CHC (α-cyano-4-hydroxycinnamic acid) not only block tumor cell energy metabolism but also increase sensitivity to reactive oxygen species, enhancing the cytotoxic effect on tumor cells. Furthermore, combining the treatment strategies with FMD condition control can further inhibit cancer cell energy metabolism, achieving significant synergistic anti-tumor therapy. Both in vitro and in vivo experiments confirm that ZTCOF with SDT/CDT/starvation can achieve effective tumor suppression and destruction. This work provides theoretical and technical support for anti-tumor multimodal synergistic therapy., (© 2024 Wiley‐VCH GmbH.)

Amplifying oxidative stress within tumor cells can effectively inhibit the growth and metastasis of triple-negative breast cancer (TNBC). Therefore, the development of innovative nanomedicines that can effectively disrupt the redox balance represents a promising yet challenging therapeutic strategy for TNBC. In this study, an oxidative stress amplifier, denoted as PBCH, comprising PdAg mesoporous nanozyme and a CaP mineralized layer, loaded with GSH inhibitor L-buthionine sulfoximine (BSO), and further surface-modified with hyaluronic acid that can target CD44, is introduced. In the acidic tumor microenvironment, Ca 2+ is initially released, thereby leading to mitochondrial dysfunction and eventually triggering apoptosis. Additionally, BSO suppresses the synthesis of intracellular reduced GSH and further amplifies the level of oxidative stress in cancer cells. Furthermore, PdAg nanozyme can be activated by near-infrared light to induce photothermal and photodynamic effects, causing a burst of ROS and simultaneously promoting cell apoptosis via provoking immunogenic cell death. The high-performance therapeutic effects of PBCH, based on the synergistic effect of aforementioned multiple oxidative damage and photothermal ablation, are validated in TNBC cells and animal models, declaring its potential as a safe and effective anti-tumor agent. The proposed approach offers new perspectives for precise and efficient treatment of TNBC., (© 2024 Wiley‐VCH GmbH.)

Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8 + T cells infiltration. All above processes together contribute to the increasing survival rate of tumor-bearing mice by nearly 4-folds. This work presented a unique design for the biological application of one-step synergistic therapy of bladder cancer., (© 2024 Wiley‐VCH GmbH.)

Synergistic therapy has become the major therapeutic method for malignant tumors in clinical. Photodynamic therapy (PDT) and radiotherapy (RT) always combine together because of their identical anti-tumor mechanisms, that is reactive oxygen species are generated by the use of radiosensitizers after irradiation by X-ray to efficiently kill cancer cells, PDT also follows similar mechanism. Full exposure of energy-absorbing species in nanomaterials to X-ray or near-infrared light irradiation makes the energy interchange between nanomaterials and surrounding H 2 O or dissolved oxygen easier, however, it remains challenging. Herein, an ultrathin two-dimensional (2D) nanosheet (NS) is developed, Bi 2 O 2 CO 3 , doped with lanthanide ions to give out upconversion luminescence, where the high Z elements Bi, Yb, and Er promote the radio-sensitizing effect. To the surprise, lanthanide activator ions gave out completely different luminescence properties compared with traditional upconversion nanoparticles. Less dopant of Er ions in nanosheets lattice resulted in brighter red emission, which provides more efficient PDT. Under RT/PDT combined treatment, NS shows a good tumor growth-inhibiting effect. In addition, synergistic therapy requires lower radiation dose than conventional radiotherapy and lower light power than single photodynamic therapy, thus greatly reducing radiation damage caused by RT and thermal damage caused by PDT., (© 2024 Wiley‐VCH GmbH.)

Despite the advantages of high tissue penetration depth, selectivity, and non-invasiveness of photothermal therapy for cancer treatment, developing NIR-II photothermal agents with desirable photothermal performance and advanced theranostics ability remains a key challenge. Herein, a universal surface modification strategy is proposed to effectively improve the photothermal performance of vanadium carbide MXene nanosheets (L-V 2 C) with the removal of surface impurity ions and generation of mesopores. Subsequently, MnO x coating capable of T1-weighted magnetic resonance imaging can be in situ formed through surface redox reaction on L-V 2 C, and then, stable nanoplatforms (LVM-PEG) under physiological conditions can be obtained after further PEGylation. In the tumor microenvironment irradiated by NIR-II laser, multivalent Mn ions released from LVM-PEG, as a reversible electronic station, can consume the overexpression of glutathione and catalyze a Fenton-like reaction to produce ·OH, resulting in synchronous cellular oxidative damage. Efficient synergistic therapy promotes immunogenic cell death, improving tumor-related immune microenvironment and immunomodulation, and thus, LVM-PEG can demonstrate high accuracy and excellent anticancer efficiency guided by multimodal imaging. As a result, this study provides a new approach for the customization of 2D surface strategies and the study of synergistic therapy mechanisms, highlighting the application of MXene-based materials in the biomedical field., (© 2024 Wiley‐VCH GmbH.)

Copper is indispensable to organisms, while its homeostatic imbalance may interference normal cellular physiological processes and even induce cell death. Artificially regulating cellular copper content provides a viable strategy to activate antineoplastic effect. In light of this, a copper ions homeostasis perturbator (CuP-CL) with cinnamaldehyde (Cin) packaging and thermosensitive liposome coating is reported. Following laser exposure, the doping of Cu 2+ in polydopamine initiates enhanced photothermal therapy (PTT) and unlocks the outer layer of liposome, leading to the release of copper ions and Cin in tumor microenvironment with mild acidity and high glutathione (GSH) levels. The liberative Cu 2+ can evoke cuproptosis and chemodynamic therapy (CDT). Meanwhile, leveraging the merits of H 2 O 2 supply and GSH consumption, Cin serves as a tumor microenvironment regulator to amplify Cu 2+ mediated cuproptosis and CDT. Additionally, the positive feedback effects of "laser-triggered PTT, PTT accelerates reactive oxygen species (ROS) generation, ROS amplifies lipid peroxide (LPO) accumulation, LPO mediates heat shock proteins (HSPs) clearance, down-regulated HSPs promote PTT" entailed the overall benefit to therapeutic outcomes. Both in vitro and in vivo results corroborate the remarkable antineoplastic performance of CuP-CL by the synergy of cuproptosis/CDT/PTT. Collectively, based on the three-pronged approach, this work plots a viable multimodal regimen for cancer therapy., (© 2024 Wiley‐VCH GmbH.)

Photothermal agents (PTAs) with desirable near-infrared (NIR) absorption and excellent photothermal conversion efficiency (PCE) are ideal candidates for cancer treatment. However, numerous PTAs still require high-intensity and long-duration laser irradiation to completely ablate the tumor during the photothermal therapy (PTT) process, resulting in light damage to healthy skin and tissue as well as limiting their biomedical applications. Integrating intense NIR absorption and high PCE into a single small-molecule PTA is an important prerequisite for realizing efficient PTT, but is a serious challenge. Herein, a series of donor-acceptor type PTAs (CC1 to NC4) are designed through a molecular engineering strategy. Theoretical calculations and experimental results show that the NIR absorption and photothermal effect from CC1 to NC4 are significantly enhanced as expected. Notably, NC4 nanoparticles exhibit intense NIR absorption, superhigh PCE of up to 88.9% for PTT, photoacoustic imaging and photothermal imaging, and effective reactive oxygen species generation for photodynamic therapy (PDT). The superior PTT/PDT synergistic phototherapeutic efficacy is well demonstrated by the complete elimination of tumor in vivo upon one-time, low-intensity, and short-duration laser irradiation (808 nm, 330 mW cm -2 , and 3 min). This work provides a valuable guideline for rational design of PTAs for cancer phototherapy., (© 2024 Wiley‐VCH GmbH.)

Postoperative tumor recurrence and wound infection remain significant clinical challenges in surgery, often requiring adjuvant therapies. The combination treatment of photothermal therapy (PTT) and chemodynamic therapy (CDT) has proven to be effective in cancer treatment and wound infection. However, the hyperthermia during PTT increases the risk of normal tissue damage, severely impeding its application. Moreover, the efficacy of CDT is limited by insufficient hydrogen peroxide (H 2 O 2 ) and excessive glutathione (GSH) levels at tumor or infection sites. Herein, an injectable and multifunctional CuO 2 @Au hydrogel system (CuO 2 @Au Gel) is developed for synergistic CDT and low-temperature PTT (LTPTT) to prevent tumor recurrence and bacterial wound infections. CuO 2 @Au Gel is constructed by embedding therapeutic CuO 2 @Au into low-melting point agarose hydrogel. In vitro and in vivo experiments confirm that the CuO 2 @Au in CuO 2 @Au Gel is capable of self-supplying H 2 O 2 and depleting GSH, exhibiting effective CDT effect in acidic tumor or bacterial infected microenvironment. Additionally, it exhibits favorable photothermal conversion ability, inducing localized temperature elevation and synergistically enhancing CDT efficiency. The prepared CuO 2 @Au Gel demonstrates efficient tumor ablation capability in post-surgery recurrence mouse models and exhibits promising anti-infective efficiency in bacterial infection wound models, indicating significant potential in adjuvant therapy for post-surgical treatment and recovery., (© 2024 Wiley‐VCH GmbH.)

The development of nanoassemblies, activated by the tumor microenvironment, capable of generating photothermal therapy (PTT) and amplifying the "ROS (·OH) storm," is essential for precise and effective synergistic tumor treatment. Herein, an innovative cascade-amplified nanotheranostics based on biodegradable Pd-BSA-GOx nanocomposite for NIR-II photoacoustic imaging (PAI) guides self-enhanced NIR-II PTT/chemodynamic therapy (CDT)/starvation synergistic therapy. The Pd-BSA-GOx demonstrates the ability to selectively convert overexpressed H 2 O 2 into strongly toxic ·OH by a Pd/Pd 2+ -mediated Fenton-like reaction at a lower pH level. Simultaneously, the GOx generates H 2 O 2 and gluconic acid, effectively disrupting nutrient supply and instigating tumor starvation therapy. More importantly, the heightened levels of H 2 O 2 and increased acidity greatly enhance the Fenton-like reactivity, generating a significant "·OH storm," thereby achieving Pd 2+ -mediated cascade-amplifying CDT. The specific PTT facilitated by undegraded Pd accelerates the Fenton-like reaction, establishing a positive feedback process for self-enhancing synergetic PTT/CDT/starvation therapy via the NIR-II guided-PAI. Therefore, the multifunctional nanotheranostics presents a simple and versatile strategy for the precision diagnosis and treatment of tumors., (© 2024 Wiley‐VCH GmbH.)

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Ferroptosis is a new form of regulated cell death featuring iron-dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis-based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis-based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis-related signaling pathways. Encouraged by the rapid development of ferroptosis-driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis-induced tumor therapy, including metal complexes, metal-based nanoparticles, and metal-free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted., (© 2024 Wiley‐VCH GmbH.)

High intensity focused ultrasound (HIFU) has attracted considerable attention as a noninvasive, efficient, and economic therapeutic modality for solid tumors. However, HIFU surgery has its intrinsic limitation in completely ablating tumors, leading to residual tumor tissue. Furthermore, the severely hypoxic environment ensuring after surgery can exacerbate the unrestricted proliferation and metabolism of residual tumor cells, leading to tumor recurrence and metastasis. To address these limitations, a versatile HIFU-specific metal-organic framework nanosystem (called ADMOFs) is developed by coordinating hypoxia-activated prodrug AQ4N, Mn 2+ , and DOX based on the postoperative response to changes in the tumor microenvironment. ADMOFs loaded with AQ4N/Mn 2+ exhibited remarkable tumor-targeting behavior in vivo and enhanced photoacoustic/magnetic resonance imaging effects, enabling more accurate guidance for HIFU surgery. After surgery, the ADMOFs exploited the severely hypoxic tumor environment induced by HIFU, overcoming hypoxia-associated drug resistance, and inducing immunogenic cell death. Finally, it effectively inhibited tumor growth and eliminated lung metastasis. Transcriptome studies revealed that this strategy significantly up-regulated genes involved in apoptosis, cell cycle, and HIF-1 signaling pathway while downregulating genes related to tumor proliferation and metastasis. These findings suggest that combining hypoxia-activated chemo-immunotherapy with HIFU is a promising strategy for enhancing cancer theranostics., (© 2023 Wiley‐VCH GmbH.)

In the course of antitumor therapy, the complex tumor microenvironment and drug-mediated changes in cell signaling and biological processes lead to drug resistance. The effect of sorafenib is greatly limited by the specific tumor microenvironment induced by antiangiogenic therapy and ferroptosis resistance induced by the upregulation of nuclear factor erythroid-2 related factor 2 (NRF2). In this study, a pH responsive and amphiphilic hyperbranched polyglycerol, HDP, is synthesized based on a co-graft click chemistry pathway. This nano-scale carrier provides excellent drug-loading capacity, storing stability and pH responsibility, and effectively co-delivery of sorafenib and siRNA. Sorafenib and siNRF2 plays a greatly synergistic effect in inducing reactive oxygen species (ROS), iron overloading, depleting glutathione (GSH), and promoting lipid peroxidation. Importantly, verified in two different animal experiments, HDP-ss (HDP loaded with both siNRF2 and sorafenib) presents a superior anti-tumor effect, by achieving a tumor inhibition rate of ≈94%. Thus, HDP can serve as an excellent targeted delivery nanocarrier with good biocompatibility in antitumor therapy, and combined application of siNRF2 effectively improves the antitumor effect of sorafenib by overcoming NRF2-mediated ferroptosis resistance. Taken together, this study provides a novel therapeutic strategy to combat the drug resistance in antiangiogenic therapy and ferroptosis., (© 2023 Wiley‐VCH GmbH.)

Cytochrome C (Cytc) has received considerable attention due to its ability to induce tumor apoptosis and generate oxygen to improve photodynamic therapy (PDT) efficiency. However, the damage to normal tissues caused by nonspecific accumulation of Cytc limits its application. Herein, in order to reduce its toxicity to normal tissues while retaining its activity, a charge conversional biomimetic nanosystem (CA/Ce6@MSN-4T1) is proposed to improve the tumor targeting ability and realize controlled release of Cytc in the tumor microenvironment. This nanosystem is constructed by coating tumor cell membrane on mesoporous silica nanoparticles coloaded with a photosensitizer (chlorin e6, Ce6) and the citraconic anhydride conjugated Cytc (CA) for synergistic photodynamic/protein therapy. The coating of the tumor cell membrane endows the nanoparticles with homologous targeting ability to the same cancer cells as well as immune escaping capability. CA undergoes charge conversion in the acidic environment of the tumor to achieve a controlled release of Cytc. The released Cytc can relieve cellular hypoxia to improve the PDT efficiency of Ce6 and can induce programmed cell death. Both in vitro and in vivo studies demonstrated that CA/Ce6@MSN-4T1 can efficiently inhibit the growth of tumors through synergistic photodynamic/protein therapy, and meanwhile show reduced side effects on normal tissues., (© 2023 Wiley‐VCH GmbH.)

Chemodynamic therapy (CDT) is a particular oncological therapeutic strategy by generates the highly toxic hydroxyl radical (•OH) from the dismutation of endogenous hydrogen peroxide (H 2 O 2 ) via Fenton or Fenton-like reactions. However, single CDT therapies have been limited by unsatisfactory efficacy. Enhanced chemodynamic therapy (ECDT) triggered by near-infrared (NIR) is a novel therapeutic modality based on light energy to improve the efficiency of Fenton or Fenton-like reactions. However, the limited penetration and imaging capability of the visible (400-650 nm) and traditional NIR-I region (650-900 nm) light-amplified CDT restrict the prospects for its clinical application. Combined with the high penetration/high precision imaging characteristics of the second near-infrared (NIR-II,) nanoplatform, it is expected to kill deep tumors efficiently while imaging the treatment process in real-time, and more notably, the NIR-II region radiation with wavelengths above 1000 nm can minimize the irradiation damage to normal tissues. Such NIR-II ECDT nanoplatforms have greatly improved the effectiveness of CDT therapy and demonstrated extraordinary potential for clinical applications. Accordingly, various strategies have been explored in the past years to improve the efficiency of NIR-II Enhanced CDT. In this review, the mechanisms and strategies used to improve the performance of NIR-II-enhanced CDT are outlined., (© 2023 Wiley‐VCH GmbH.)

Photodynamic therapy (PDT) with aggregation-induced emission (AIE) photosensitizers (PSs) is a promising therapeutic strategy to achieve better anticancer results. However, eradicating solid tumors completely by PDT alone can be difficult owing to the inherent drawbacks of this treatment, and the combination of PDT with other therapeutic modalities provides opportunities to achieve cooperative enhancement interactions among various treatments. Herein, this work presents the construction of a biocompatible nanocomposite, namely CaO 2 @DOX@ZIF@ASQ, featuring light-responsive reactive oxygen species (ROS) generation and tumor-targeting oxygen and hydrogen peroxide discharge, as well as controlled doxorubicin (DOX) and copper ion release, thus allowing the combined PDT/CT/CDT effect by AIE PS-enhanced PDT, DOX-based chemotherapy (CT), and copper-involved Fenton-like reaction-driven chemodynamic therapy (CDT). In vitro and in vivo studies verify that the generation of both ROS and O 2 by this nanomedicine, stimulated by light, exhibits superior anticancer efficacy, alleviating tumor hypoxia and achieving synergistic PDT/CT/CDT therapeutic effect. This multifunctional nanomedicine remarkably suppresses the tumor growth with minimized systemic toxicity, providing a new strategy for constructing multimodal PDT/CT/CDT therapeutic systems to overcome hypoxia limitations, and potentially increase the antitumor efficacy at lower doses of PSs and chemotherapeutic drugs, thus minimizing potential toxicity to non-malignant tissues., (© 2023 Wiley‐VCH GmbH.)

Cancer has been the most deadly disease, and 13 million cancer casualties are estimated to occur each year by 2030. Gold nanoparticles (AuNPs)-based photothermal therapy (PTT) has attracted great interest due to its high spatiotemporal controllability and noninvasiveness. Due to the trade-off between particle size and photothermal efficiency of AuNPs, rational design is needed to realize aggregation of AuNPs into larger particles with desirable NIR adsorption in tumor site. Exploiting the bioorthogonal "Click and Release" (BCR) reaction between iminosydnone and cycloalkyne, aggregation of AuNPs can be achieved and attractively accompanied by the release of chemotherapeutic drug purposed to photothermal synergizing. We synthesize iminosydnone-lonidamine (ImLND) as a prodrug and choose dibenzocyclooctyne (DBCO) as the trigger of BCR reaction. A PEGylated AuNPs-based two-component nanoplatform consisting of prodrug-loaded AuNPs-ImLND and tumor-targeting peptide RGD-conjugated AuNPs-DBCO-RGD is designed. In the therapeutic regimen, AuNPs-DBCO-RGD are intravenously injected first for tumor-specific enrichment and retention. Once the arrival of AuNPs-ImLND injected later at tumor site, highly photothermally active nanoaggregates of AuNPs are formed via the BCR reaction between ImLND and DBCO. The simultaneous release of lonidamine further enhanced the therapeutic performance by sensitizing cancer cells to PTT., (© 2024 Wiley-VCH GmbH.)

Cancer is one of the most serious diseases challenging human health and life span. Cancer has claimed millions of lives worldwide. Early diagnosis and effective treatment of cancer are very important for the survival of patients. In recent years, 2D nanomaterials have shown great potential in the development of anticancer treatment by combining their inherent physicochemical properties after surface modification. 2D nanomaterials have attracted great interest due to their unique nanosheet structure, large surface area, and extraordinary physicochemical properties. This article reviews the advantages and application status of emerging 2D nanomaterials for targeted tumor synergistic therapy compared with traditional therapeutic strategies. In order to investigate novel potential anticancer strategies, this paper focuses on the surface modification, cargo delivery capability, and unique optical properties of emerging 2D nanomaterials. Finally, the current problems and challenges in cancer treatment are summarized and prospected., (© 2023 Wiley-VCH GmbH.)

Endogenous essential metal ions play an important role in many life processes, especially in tumor development and immune response. The approval of various metallodrugs for tumor therapy brings more attention to the antitumor effect of metal ions. With the deepening understanding of the regulation mechanisms of metal ion homeostasis in vivo, breaking intracellular metal ion homeostasis becomes a new means to inhibit the proliferation of tumor cells and activate antitumor immune response. Diverse nanomedicines with the loading of small molecular ion regulators or metal ions have been developed to disrupt metal ion homeostasis in tumor cells, with higher safety and efficiency than free small molecular ion regulators or metal compounds. This comprehensive review focuses on the latest progress of various intracellular metal ion homeostasis regulation-based nanomedicines in tumor therapy including calcium ion (Ca 2+ ), ferrous ion (Fe 2+ ), cuprous ion (Cu + ), managanese ion (Mn 2+ ), and zinc ion (Zn 2+ ). The physiological functions and homeostasis regulation processes of ions are summarized to guide the design of metal ion regulation-based nanomedicines. Then the antitumor mechanisms of various ions-based nanomedicines and some efficient synergistic therapies are highlighted. Finally, the challenges and future developments of ion regulation-based antitumor therapy are also discussed, hoping to provide a reference for finding more effective metal ions and synergistic therapies., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Tumor microenvironment (TME)-responsive nanozyme-catalyzed cancer therapy shows great potential due to its specificity and efficiency. However, breaking the self-adaption of tumors and improving the sustainable remodeling TME ability remains a major challenge for developing novel nanozymes. Here, a rapid method is developed first to synthesize unprecedented trimetalic nanozyme (AuMnCu, AMC) with a targeting peptide (AMCc), which exhibits excellent peroxidase-like, catalase-like, and glucose oxidase-like activities. The released Cu and Mn ions in TME consume endogenous H 2 O 2 and produce O 2 , while the AMCccatalyzes glucose oxidation reaction to generate H 2 O 2 and gluconic acid, which achieves the starvation therapy by depleting the energy and enhances the chemodynamic therapy effect by lowering the pH of the TME and producing extra H 2 O 2 . Meanwhile, the reactive oxygen species damage is amplified, as AMCc can constantly oxidize intracellular reductive glutathione through the cyclic valence alternation of Cu and Mn ions, and the generated Cu + elevate the production of ·OH from H 2 O 2 . Further studies depict that the well-designed AMCc exhibits the excellent photothermal performance and achieves TME-responsive sustainable starvation/photothermal-enhanced chemodynamic synergistic effects in vitro and in vivo. Overall, a promising approach is demonstrated here to design "all-in-one" nanozyme for theranostics by remodeling the TME., (© 2023 Wiley-VCH GmbH.)

The photothermal performance of black phosphorus (BP) in the near infrared (NIR)-II bio-window (1000-1500 nm) is low, which limits its biomedical applications. Herein, ultrasmall nickel phosphide quantum dots (Ni 2 P QDs) are synthesized with BP quantum dots (BPQDs) as the template by topochemical transformation. The size of Ni 2 P QDs is ≈3.5 nm, similar to that of BPQDs, whereas the absorption and photothermal conversion efficiency of Ni 2 P QDs at 1064 nm (43.5%) are significantly improved compared with those of BPQDs. To facilitate in vivo applications, an Ni 2 P QDs-based liposomal nano-platform (Ni 2 P-DOX@Lipo-cRGD) is designed by incorporation of Ni 2 P QDs and doxorubicin (DOX) into liposomal bilayers and the interior, respectively. The encapsulated DOX is responsively released from liposomes upon 1064-nm laser irradiation owing to the photothermal effect of Ni 2 P QDs, and the drug release rate and amount are controlled by the light intensity and exposure time. In vivo, experiments show that Ni 2 P-DOX@Lipo-cRGD has excellent tumor target capability and biocompatibility, as well as complete tumor ablation through the combination of photothermal therapy and chemotherapy. The work provides a new paradigm for the NIR-II transformation of nano-materials and may shed light on the construction of multifunctional nano-platforms for cancer treatment., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Combined chemotherapy and targeted therapy holds immense potential in the management of advanced gastric cancer (GC). GC tissues exhibit an elevated expression level of protein kinase B (AKT), which contributes to disease progression and poor chemotherapeutic responsiveness. Inhibition of AKT expression through an AKT inhibitor, capivasertib (CAP), to enhance cytotoxicity of paclitaxel (PTX) toward GC cells is demonstrated in this study. A cathepsin B-responsive polymeric nanoparticle prodrug system is employed for co-delivery of PTX and CAP, resulting in a polymeric nano-drug BPGP@CAP. The release of PTX and CAP is triggered in an environment with overexpressed cathepsin B upon lysosomal uptake of BPGP@CAP. A synergistic therapeutic effect of PTX and CAP on killing GC cells is confirmed by in vitro and in vivo experiments. Mechanistic investigations suggested that CAP may inhibit AKT expression, leading to suppression of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Encouragingly, CAP can synergize with PTX to exert potent antitumor effects against GC after they are co-delivered via a polymeric drug delivery system, and this delivery system helped reduce their toxic side effects, which provides an effective therapeutic strategy for treating GC., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The effective and targeted treatment of resistant cancer cells presents a significant challenge. Targeting cell ferroptosis has shown remarkable efficacy against apoptosis-resistant tumors due to their elevated iron metabolism and oxidative stress levels. However, various obstacles have limited its effectiveness. To overcome these challenges and enhance ferroptosis in cancer cells, we have developed a self-powered photodynamic therapeutic tablet that integrates a ferroptosis inducer (FIN), imidazole ketone erastin (IKE). FINs augment the sensitivity of photodynamic therapy (PDT) by increasing oxidative stress and lipid peroxidation. Furthermore, they utilize the Fenton reaction to supplement oxygen, generating a greater amount of reactive oxygen species (ROS) during PDT. Additionally, PDT facilitates the release of iron ions from the labile iron pool (LIP), accelerating lipid peroxidation and inducing ferroptosis. In vitro and in vivo experiments have demonstrated a more than 85% tumor inhibition rate. This synergistic treatment approach not only addresses the limitations of inadequate penetration and tumor hypoxia associated with PDT but also reduces the required medication dosage. Its high efficiency and specificity towards targeted cells minimize adverse effects, presenting a novel approach to combat clinical resistance in cancer treatment., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Due to the limitations of H 2 O 2 under physiological conditions and defective activity, nanozyme-catalyzed therapy for infected diabetic wound healing is still a huge challenge. Here, this work designs a novel multifunctional hybrid glucose oxidase (GOx)-CeO 2 @black phosphorus (BP)/Apt nanosheet that features GOx and CeO 2 dual enzyme loading with photothermal enhancement effect and targeting ability for the treatment of infected wounds in type II diabetic mice. Combined with the photothermal properties of the BP nanosheets, the cascade nanozyme effect of GOx and CeO 2 is extremely enhanced. The synergistic effect of peroxidase activity and photothermal therapy with targeting aptamer allows for overcoming the catalytic defects of nanozyme and significantly improving in vitro bacterial inhibition rate with 99.9% and 97.8% for Staphylococcus aureus and Escherichia coli, respectively, as well as enhancing in vivo antibacterial performance with the lowest wound remained (0.05%), reduction of infiltration inflammatory cells, and excellent biocompatibility. Overall, this work builds a nanodelivery system with a powerful therapeutic approach, incorporating self-supplying H 2 O 2 synergistic photothermal and real-time wound monitoring effect, which holds profound potential as a clinical treatment for infected diabetic wounds., (© 2023 Wiley-VCH GmbH.)

Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor-1α (HIF-1α) expression and promote the activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for liver fibrosis is extremely lacking. Herein, a safe and effective method is established to downregulate the expression of HIF-1α in HSCs via targeted delivery of VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) HIF-1α small interfering RNA (HIF-1α-siRNA). Due to the presence of lipase in the liver, the reversible release of siRNA can be promoted to complete the transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enable trigger the water splitting process to produce O 2 under near-infrared (NIR) irradiation, thereby improving the hypoxic environment of the liver fibrosis site and maximizing the downregulation of HIF-1α expression to improve the therapeutic effect, as demonstrated in liver fibrosis mice. Such combination therapy can inhibit the activation of HSCs via HIF-1α-mediated TGF-β1/Smad pathway, achieving outstanding therapeutic effects in liver fibrosis mice. In conclusion, this study proposes a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF-1α at lesion site., (© 2023 Wiley-VCH GmbH.)

Accurate location and efficient treatment of diseases by multifunctional nanoplatforms are appealing but face great challenges. Theranostic agents through the physical combination of different functional nanoparticles are demonstrated to be effective. Yet, the complicated biological environment often leads to ambiguous fates of each agent, which fails to keep the behaviors of imaging and therapeutic components in a simultaneous manner. Herein, "integrated" theranostic NPs, Gd-doped CuWO 4 (CWG) with strong near-infrared (808 nm) absorption, the longest absorption peak of reported CuWO 4 , located in the biological transparent window, are constructed. The single doping of trace amount of Gd not only endows them with a distinguished magnetic resonance imaging capability (r 1 = 12.01 mM -1 s -1 ), but also concurrently imposes great effect on the valence states of matrix ion (Cu), as evidenced by theoretical calculation results. The charge distribution shift of Cu would facilitate ·OH generation, beneficial for chemodynamic therapy (CDT). Moreover, CWG NPs display remarkable photoacoustic (PA) and computed tomography (CT) imaging capabilities (S = 10.33 HU mM -1 ). Such integrated theranostics afford a paradigm for multimodal imaging-guided synergistic therapy with all-in-one single nanoparticle., (© 2023 Wiley-VCH GmbH.)

With the continuous updating of cancer treatment methods and the rapid development of precision medicine in recent years, there are higher demands for advanced and versatile drug delivery systems. Scientists are committed to create greener and more effective nanomedicines where the carrier is no longer limited to a single function of drug delivery. Polyphenols, which can act as both active ingredients and fundamental building blocks, are being explored as potential multifunctional carriers that are efficient and safe for design purposes. Due to their intrinsic anticancer activity, phenolic compounds have shown surprising expressiveness in ablation of tumor cells, overcoming cancer multidrug resistance (MDR), and enhancing immunotherapeutic efficacy. This review provides an overview of recent advances in the design, synthesis, and application of versatile polyphenol-based nanosystems for cancer therapy in various modes. Moreover, the merits of polyphenols and the challenges for their clinical translation are also discussed, and it is pointed out that the novel polyphenol delivery system requires further optimization and validation., (© 2023 Wiley-VCH GmbH.)

The combination of chemo/chemodynamic therapy is a promising strategy for improving antitumor efficacy. Herein, metal-phenolic network nanoparticles (NPs) self-assembled from copper ions and gallic acid (Cu-GA) are developed to evoke apoptosis and cuproptosis for synergistic chemo/chemodynamic therapy. The Cu-GA NPs are biodegraded in response to the highly expressed glutathione (GSH) in tumor cells, resulting in the simultaneous release of Cu + and GA. The intracellular GSH content is dramatically reduced by the released GA, rendering the tumor cells incapable of scavenging reactive oxygen species (ROS) and more susceptible to cuproptosis. Meanwhile, ROS levels within the tumor cells are significantly increased by the Fenton-like reaction of released Cu + , which disrupts redox homeostasis and achieves apoptosis-related chemodynamic therapy. Moreover, massive accumulation of Cu + in the tumor cells further induces aggregation of lipoylated dihydrolipoamide S-acetyltransferase and downregulation of iron-sulfur cluster protein, activating cuproptosis to enhance the antitumor efficacy of Cu-GA NPs. The experiments in vivo further demonstrate that Cu-GA NPs exhibited the excellent biosafety and superior antitumor capacity, which can efficiently inhibit the growth of tumors due to the activation by the tumor specific GSH and hydrogen peroxide. These Cu-based metal-phenolic network NPs provide a potential strategy to build up efficient and safe cancer therapy., (© 2023 Wiley-VCH GmbH.)

Critical limb ischemia, the final course of peripheral artery disease, is characterized by an insufficient supply of blood flow and excessive oxidative stress. H 2 S molecular therapy possesses huge potential for accelerating revascularization and scavenging intracellular reactive oxygen species (ROS). Moreover, it is found that BMP6 is the most significantly up-expressed secreted protein-related gene in HUVECs treated with GYY4137, a H 2 S donor, based on the transcriptome analysis. Herein, a UIO-66-NH 2 @GYY4137@BMP6 co-delivery nanoplatform to strengthen the therapeutic effects of limb ischemia is developed. The established UIO-66-NH 2 @GYY4137@BMP6 nanoplatform exerts its proangiogenic and anti-oxidation functions by regulating key pathways. The underlying molecular mechanisms of UIO-66-NH 2 @GYY4137@BMP6 dual-loading system lie in the upregulation of phosphorylated YAP/TAZ and Jun to promote HUVECs proliferation and downregulation of phosphorylated p53/p21 to scavenge excessive ROS. Meanwhile, laser-doppler perfusion imaging (LDPI), injury severity evaluation, and histological analysis confirm the excellent therapeutic effects of UIO-66-NH 2 @GYY4137@BMP6 in vivo. This work may shed light on the treatment of critical limb ischemia by regulating YAP, Jun, and p53 signaling pathways based on gas-protein synergistic therapy., (© 2023 Wiley-VCH GmbH.)

Sepsis is a highly heterogeneous syndrome normally characterized by bacterial infection and dysregulated systemic inflammatory response that leads to multiple organ failure and death. Single anti-inflammation or anti-infection treatment exhibits limited survival benefit for severe cases. Here a biodegradable tobramycin-loaded magnesium micromotor (Mg-Tob motor) is successfully developed as a potential hydrogen generator and active antibiotic deliverer for synergistic therapy of sepsis. The peritoneal fluid of septic mouse provides an applicable space for Mg-water reaction. Hydrogen generated sustainably and controllably from the motor interface propels the motion to achieve active drug delivery along with attenuating hyperinflammation. The developed Mg-Tob motor demonstrates efficient protection from anti-inflammatory and antibacterial activity both in vitro and in vivo. Importantly, it prevents multiple organ failure and significantly improves the survival rate up to 87.5% in a high-grade sepsis model with no survival, whereas only about half of mice survive with the individual therapies. This micromotor displays the superior therapeutic effect of synergistic hydrogen-chemical therapy against sepsis, thus holding great promise to be an innovative and translational drug delivery system to treat sepsis or other inflammation-related diseases in the near future., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

To strengthen the antitumor efficacy and avoid toxicity to normal cells of cisplatin and triptolide, herein, an acid and glutathione (GSH) dual-controlled nanoplatform for enhanced cancer treatment through the synergy of both "1+1" apoptosis and "1+1" ferroptosis is designed. Remarkably, ZIF8 in response to tumor microenvironment enhances drug targeting and protects drugs from premature degradation. Meanwhile, the Pt IV  center can be easily reduced to cisplatin because of the large amount of GSH, thus liberating the triptolide as the coordinated ligand. The released cisplatin and hemin in turn boost the tumor cell "1+1" apoptosis through chemotherapy and photodynamic therapy, respectively. Furthermore, GSH reduction through Pt IV  weakens the activation of glutathione peroxidase 4 (GPX4) effectively. The released triptolide can inhibit the expressions of GSH by regulating nuclear factor E2 related factor 2 (Nrf2), further promoting membrane lipid peroxidation, thus "1+1" ferroptosis can be achieved. Both in vitro and in vivo results demonstrate that the nanosystem can not only perform superior specificity and therapeutic outcomes but also reduce the toxicity to normal cells/tissues of cisplatin and triptolide effectively. Overall, the prodrug-based smart system provides an efficient therapeutic strategy for cancer treatment by virtue of the effect of enhanced "1+1" apoptosis and "1+1" ferroptosis therapies., (© 2023 Wiley-VCH GmbH.)

Cuproptosis, a kind of newly recognized cell death modality, shows enormous prospect in cancer treatment. The inducer of cuproptosis has more advantages in tumor therapy, especially that can trigger cuproptosis and chemodynamic therapy (CDT) simultaneously. However, cuproptosis is restricted to the deficiency of intracellular copper ions and the nonspecific delivery of copper-based ionophores. Therefore, high level delivery, responsive release, and utilizing synergistic-function of inducer become the key on cuproptosis-based oncotherapy. In this work, a cascade nanosystem is constructed for enhanced cuproptosis and CDT. In the weak acidic environment of tumor cells, DNA, zinc ions, and Cu + can release from the nanosystem. Since Cu + having superior performance in mediating both Fenton-like reaction and cuproptosis, the released Cu + induces cuproptosis and CDT efficiently, accompanied by Cu 2+ generation. Then Cu 2+ can be converted into Cu + partially by glutathione (GSH) to from a Cu + supply loop and ensure the synergistic action. Meanwhile, the consumption of GSH also contributes to cuproptosis and CDT in return. Finally, DNA and Zn 2+ form DNAzyme to shear catalase-related RNA, resulting in the accumulation of hydrogen peroxide and further enhancing combination therapy. These results provide a promising nanotherapeutic platform and may inspire the design for potential cancer treatment based on cuproptosis., (© 2023 Wiley-VCH GmbH.)

The fast renal clearance of hydrophilic small molecular anticancer drugs and ultrasmall nanoparticles (NPs) results in the low utilization rate and certain side effects, thus improving the tumor targeting is highly desired but faces great challenges. A novel and general β-cyclodextrin (CD) aggregation-induced assembly strategy to fabricate doxorubicin (DOX) and CD-coated NPs (such as Au) co-encapsulated pH-responsive nanocomposites (NCs) is proposed. By adding DOX×HCl and reducing pH in a reversed microemulsion system, hydrophilic CD-coated AuNPs rapidly assemble into large NCs. Then in situ polymerization of dopamine and sequentially coordinating with Cu 2+ on the surface of NCs provide extra weak acid responsiveness, chemodynamic therapy (CDT), and improved biocompatibility as well as stability. The subsequent tumor microenvironment responsive dissociation notably improves their passive tumor targeting, bioavailability, imaging, and therapeutic capabilities, as well as facilitates their internalization by tumor cells and metabolic clearance, thereby reducing side effects. The combination of polymerized dopamine and assembled AuNPs reinforces photothermal capability, thus further boosting CDT through thermally amplifying Cu-catalyzed Fenton-like reaction. Both in vitro and in vivo studies confirm the desirable outcomes of these NCs as photoacoustic imaging guided trimodal (thermally enhanced CDT, photothermal therapy, and chemotherapy) synergistic tumor treatment agents with minimal systemic toxicity., (© 2023 Wiley-VCH GmbH.)

Ferroptosis is identified as a novel type of cell death with distinct properties involved in physical conditions and various diseases, including cancers. It is considered that ferroptosis provides a promising therapeutic strategy for optimizing oncotherapy. Although erastin is an effective ferroptosis trigger, the potential of its clinical application is largely restricted by its poor water solubility and concomitant limitations. To address this issue, an innovative nanoplatform (PE@PTGA) that integrated protoporphyrin IX (PpIX) and erastin coated with amphiphilic polymers (PTGA) to evoke ferroptosis and apoptosis is constructed and exemplified using an orthotopic hepatocellular carcinoma (HCC) xenograft mouse model as a paradigm. The self-assembled nanoparticles can enter HCC cells and release PpIX and erastin. With light stimulation, PpIX exerts hyperthermia and reactive oxygen species to inhibit the proliferation of HCC cells. Besides, the accumulated reactive oxygen species (ROS) can further promote erastin-induced ferroptosis in HCC cells. In vitro and in vivo studies reveal that PE@PTGA synergistically inhibits tumor development by stimulating both ferroptosis- and apoptosis-related pathways. Moreover, PE@PTGA has low toxicity and satisfactory biocompatibility, suggesting its promising clinical benefit in cancer treatments., (© 2023 Wiley-VCH GmbH.)

The fast conversion of hydrogen peroxide (H 2 O 2 ) into reactive oxygen species (ROS) at tumor sites is a promising anticancer strategy by manipulating nanomedicines with near-infrared light in the second region (NIR-II). However, this strategy is greatly compromised by the powerful antioxidant capacity of tumors and the limited ROS generation rate of nanomedicines. This dilemma mainly stems from the lack of an effective synthesis method to support high-density copper-based nanocatalysts on the surface of photothermal nanomaterials. Herein, a multifunctional nanoplatform (MCPQZ) with high-density cuprous (Cu 2 O) supported molybdenum disulfide (MoS 2 ) nanoflowers (MC NFs) is developed for the efficient killing of tumors via a potent ROS storm by an innovative method. Under NIR-II light irradiation, the ROS intensity and maximum reaction velocity (V max ) produced by MC NFs are 21.6 and 33.8 times that of the non-irradiation group in vitro, which is much higher than most current nanomedicines. Moreover, the strong ROS storm in cancer cells is efficiently formed by MCPQZ (increased by 27.8 times compared to the control), thanks to the fact that MCPQZ effectively pre-weakens the multiple antioxidant systems of cancer cells. This work provides a novel insight to solve the bottleneck of ROS-based cancer therapy., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Simultaneous photothermal ablation of multiple tumors is limited by unpredictable photo-induced apoptosis, caused by individual intratumoral differences. Here, a multi-channel lanthanide nanocomposite was used to achieve tailored synergistic treatment of multiple subcutaneous orthotopic tumors under non-uniform whole-body infrared irradiation prescription. The nanocomposite reduces intratumoral glutathione by simultaneously activating the fluorescence and photothermal channels. The fluorescence provides individual information on different tumors, allowing customized prescriptions to be made. This enables optimal induction of hyperthermia and dosage of chemo drugs, to ensure treatment efficacy, while avoiding overtherapy. With an accessional therapeutic laser system, customized synergistic treatment of subcutaneous orthotopic cancer cases with multiple tumors is possible with both high efficacy and minimized side effects., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

To overcome the limitations of doxorubicin (DOX) chemotherapy, nanomedicines that integrate additional photothermal therapy (PTT) and chemodynamic therapy (CDT) strategies are highlighted as promising alternatives for the treatment of malignant tumors. However, time-consuming preparation processes, biosafety concerns, and the bottlenecks of individual therapeutic modalities often limit the practical applications of this strategy. To address these issues, this work designs an oxygen economizer that additionally serves as a Fenton reaction amplifier through the simple assembly of epigallocatechin gallate (EGCG), pluronic F-127 (PF127), iron (III) ions, and doxorubicin (DOX) for the enhancement of synergistic PTT/CDT/chemotherapy. The resulting nanoformulation, EFPD, can target mitochondria and inhibit cell respiration to reduce O 2 consumption, thus boosting DOX-mediated H 2 O 2 generation for enhanced CDT and simultaneously improving hypoxia-limited DOX chemotherapy efficacy. Moreover, the coordination between EGCG and Fe 3+ provides EFPD with excellent photothermal conversion efficiencies (η = 34.7%) for PTT and photothermal-accelerated drug release. Experimental results indicate that EFPD-mediated synergistic enhancement of PTT/CDT/chemotherapy can achieve excellent therapeutic outcomes, including enhanced ablation of solid tumors, reduced metastasis and cardiotoxicity, and extended life spans., (© 2023 Wiley-VCH GmbH.)

Noble metal nanozymes hold promise in cancer therapy due to adjustable enzyme-like activities, unique physicochemical properties, etc. But catalytic activities of monometallic nanozyme are confined. In this study, 2D titanium carbide (Ti 3 C 2 T x )-supported RhRu alloy nanoclusters (RhRu/Ti 3 C 2 T x ) are prepared by a hydrothermal method and utilized for synergistic therapy of chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT) on osteosarcoma. The nanoclusters are small in size (3.6 nm), uniform in distribution, and have excellent catalase (CAT) and peroxidase (POD)-like activities. Density functional theory calculations show that there is a significant electron transfer interaction between RhRu and Ti 3 C 2 T x , which has strong adsorption to H 2 O 2 and is beneficial to enhance the enzyme-like activity. Furthermore, RhRu/Ti 3 C 2 T x nanozyme acts as both PTT agent for converting light into heat, and photosensitizer for catalyzing O 2 to 1 O 2 . With the NIR-reinforced POD- and CAT-like activity, excellent photothermal and photodynamic performance, the synergistic CDT/PDT/PTT effect of RhRu/Ti 3 C 2 T x on osteosarcoma is verified by in vitro and in vivo experiments. This study is expected to provide a new research direction for the treatment of osteosarcoma and other tumors., (© 2023 Wiley-VCH GmbH.)

Hypercoagulation threatens the lives of cancer patients and cancer progression. Platelet overactivation attributes to the tumor-associated hypercoagulation and maintenance of the tumor endothelial integrity, leading to limited intratumoral perfusion of nanoagents into solid tumors in spite of the enhanced penetration and retention effect (EPR). Therefore, the clinical application of nanotherapeutics in solid cancer still faces great challenges. Herein, this work establishes platelet inhibiting nanoagents based on Fe III -doped C 3 N 4 coloaded with the chemotherapy drug and the antiplatelet drug chlorogenic acid (CA), further opening tumor vascular endothelial junctions, thereby disrupting the tumor vascular endothelial integrity, and enhancing drug perfusion. Moreover, CA not only damages the cancer cells but also potentiates the cytotoxicity induced by the chemotherapy drug doxorubicin, synergistically ablating the tumor tissue. Further, the introduction of CA relieves the original causes of the hypercoagulable state such as tissue factor (TF), thrombin, and matrix metalloproteinases (MMPs) secreted by cancer cells. It is anticipated that the hypercoagulation- and platelet-inhibition strategy by integration of phenolic acid CA into chemotherapy provides insights into platelet inhibition-assisted theranostics based on nanomedicines., (© 2022 Wiley-VCH GmbH.)

Current treatments for infections caused by multidrug-resistant bacteria still remain challenging and therapeutic materials with high efficacy are of demand. Herein, a bactericidal nanocomposite was constructed by loading Roxarsone (ROX) onto nitrosylated mesoporous polydopamine (named mPDA@NO-ROX). The designed nanocomposite exhibited considerable photothermal effect and controlled NO and ROX co-delivery under the irradiation of near-infrared laser (NIR) to achieve enhanced chemo-photothermal antibacterial therapy. The in vitro antibacterial evaluation of the mPDA@NO-ROX demonstrated the effective elimination of the Gram-negative tetracycline-resistant Escherichia coil and Gram-positive methicillin-resistant Staphylococcus aureus under mild NIR irradiation compared to merely ROX loaded unmodified mPDA, indicating the NO enhanced chemo-photothermal therapy. In addition, the cytotoxicity experiments indicated that mPDA@NO-ROX exhibited only 5 % of hemolysis rate and high cell viability at 1 mg mL -1 against mammalian fibroblasts, suggesting the excellent biocompatibility. In conclusion, the mPDA@NO-ROX could be a promising candidate for anti-infection therapy of multidrug-resistant bacteria., (© 2023 Wiley-VCH GmbH.)

The redox homeostasis in tumors enhances their antioxidant defense ability, limiting reactive oxygen species mediated tumor therapy efficacy. The development of strategies for specific and continuous disruption of the redox homeostasis in tumor cells facilitates the improvement of the cancer therapeutic effect by promoting the apoptosis of tumor cells. Herein, a responsively biodegradable targeting multifunctional integrated nanosphere (HDMn-QDs/PEG-FA) is designed to enhance the anti-tumor efficacy by triggering intratumoral cascade reactions to effectively disrupt intracellular redox homeostasis. Once HDMn-QDs/PEG-FA enters tumor cells, manganese dioxide (MnO 2 ) shell on the surface of nanosphere consumes glutathione (GSH) to produce Mn 2+ , enabling enhanced chemodynamic therapy (CDT) via a Fenton-like reaction and T 1 -weighted magnetic resonance imaging. Meanwhile, the degradation of MnO 2 can also cause the fluorescence recovery of quantum dots conjugated on the surface of the shell, realizing "turn-on" fluorescence imaging. In addition, the doxorubicin is released because of the cleavage of the embedded SS bond in the hybrid core framework by GSH. A superior synergistic therapeutic efficiency combined CDT and chemotherapy is shown by HDMn-QDs/PEG-FA in vivo. The tumor-inhibition rate reaches to 94.8% and does not cause normal tissue damage due to the good targeting and tumor microenvironment-specific response., (© 2023 Wiley-VCH GmbH.)

Cuproptosis is a new form of programmed cell death and exhibits enormous potential in cancer treatment. However, reducing the undesirable Cu ion release in normal tissue and maximizing the copper-induced therapeutic effect in cancer sites are two main challenges. In this study, we constructed a photothermally triggered nanoplatform (Au@MSN-Cu/PEG/DSF) to realize on-demand delivery for synergistic therapy. The released disulfiram (DSF) chelated with Cu 2+ in situ to generate highly cytotoxic bis(diethyldithiocarbamate)copper (CuET), causing cell apoptosis, and the formed Cu + species promoted toxic mitochondrial protein aggregation, leading to cell cuproptosis. Synergistic with photothermal therapy, Au@MSN-Cu/PEG/DSF could effectively kill tumor cells and inhibit tumor growth (inhibition rate up to 80.1 %). These results provide a promising perspective for potential cancer treatment based on cuproptosis, and may also inspire the design of advanced nano-therapeutic platforms., (© 2022 Wiley-VCH GmbH.)