查找使用阿拉丁产品的科研文献

An intelligent bacterial capture nanodrug enhances immunotherapy for implant-associated infections by inducing cuproptosis-like death in bacteria

Xiaodong Hu,Yujiong Chen,Jian Huang,Shuhang Dong,Kuishuai Xu,Jiadong Cai,Tao Li,Tianrui Wang,Yingze Zhang

Implant-associated infections (IAIs), particularly those involving methicillin-resistant Staphylococcus aureus (MRSA), present a major clinical challenge due to bacterial biofilm formation and localized immunosuppression. To address this, we developed an intelligent bacterial-capture nanodrug, termed Se-MPDA-Cu-D, designed to enhance immunotherapy through a synergistic antibacterial strategy. This nanoplatform features surface-modified D-alanine for targeted binding to bacterial peptidoglycan, enabling precise localization at infection sites. Within the acidic, glutathione-rich biofilm microenvironment, the nanodrug responsively releases copper ions (Cu 2+ ) and selenium nanoparticles (Se NPs), triggering a potent chemodynamic therapy that disrupts redox homeostasis and induces a cuproptosis-like death in bacteria. This process is characterized by copper accumulation, lipid peroxidation, DNA damage, and impairment of iron‑sulfur cluster proteins. Beyond its direct antibacterial efficacy, the treatment promotes a robust Immunogenic Bacterial Death (IBD) response, activating dendritic cells, enhancing T-cell infiltration, and reversing the immunosuppressive microenvironment. Furthermore, the released bioactive ions significantly promoted osteogenic differentiation and angiogenesis in vitro. In a rat model of MRSA-infected IAIs, Se-MPDA-Cu-D NPs effectively eradicated biofilms, facilitated substantial new bone regeneration, and restored osseointegration. This multifunctional nanotherapeutic approach presents a promising strategy for combating resistant implant infections by integrating targeted bacterial capture, cuproptosis-like death, and IBD.

Mucous Permeable Nanoparticle for Inducing Cuproptosis-Like Death In Broad-Spectrum Bacteria for Nebulized Treatment of Acute Pneumonia

Huiqun Hu,Shiyuan Hua,Feng Lu,Wenting Zhang,Zengwen Zhang,Jiarong Cui,Xiaoyue Lei,Jingyan Xia,Feng Xu,Min Zhou

The emergence of antibiotic-resistant bacteria has exacerbated the challenge of treating infectious diseases. Quorum sensing (QS), a bacterial communication system regulating virulence and biofilm formation, presents a target for novel therapies. Cuproptosis death is a innovation mode of death, however, this effect may be partially inhibited by glutathione (GSH). Buthionine sulfoximine (BSO) is responsible for GSH biosynthesis and has been identified as a potential promoter of cuproptosis death. Here, Cu 2 O-BSO NPs with lung adhesion and mucus penetration ability are synthesized by incorporating BSO onto Cu 2 O, and modifying it with DOPA and PEG. Cu 2 O-BSO NPs demonstrated a broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria, making it a viable treatment option for MRSA-induced acute pneumonia. Specifically, Cu 2 O-BSO NPs can synergistically enhance bacterial cuproptosis-like death, hinder the QS system, eradicate biofilms, reduce the virulence of strains, stimulate the chemotaxis and phagocytosis of macrophages, and ultimately improve in mice with severe pneumonia. This research demonstrated the potential of Cu 2 O-BSO NPs for a wide-ranging antibacterial alternative, providing promise for addressing microbial resistance and combatting biofilm formation. Additionally, it established a target and theoretical foundation for the clinical treatment of numerous challenging cases of acute drug-resistant bacteria.

Three Birds with One Stone: Copper Ions Assisted Synergistic Cuproptosis/Chemodynamic/Photothermal Therapy by a Three-Pronged Approach

Mengyao Chen,Chang Xu,Chunhui Wang,Nan Huang,Zhixuan Bian,Yixuan Xiao,Juan Ruan,Fenyong Sun,Shuo Shi

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.

NBR1-mediated autophagic degradation of YTHDF1 curtails FDX1 translation to drive concurrent multikinase inhibitor resistance and cuproptosis tolerance

Weikai Wang,Xin Jiang,Xiaona Chen,Kaiyu Liang,Miaoqin Chen,Kaizhong Lu,Qi Wei,Yuchen Wu,Liyuan Zhu,Yuan Chen,Tianlun Hou,Jingfeng Luo,Chentao Li,Xian Wang,Hongchuan Jin,Lifeng Feng

A dual-targeting and pH/NIR-stimuli-responsive nanoassembly for enhanced cuproptosis, chemo-, and phototherapy in colorectal cancer

Xiao-Qing Ling,Xin-Yan Zhao,Qi-Yan Lv,Jun-Yang Chen,Hai-Yang Dai,Hui-Fang Cui,XiaoJie Song

Cuproptosis has gained significant attention in cancer therapy. Use of copper-overloaded combination therapy that employs a variety of cell death mechanisms has emerged as a promising avenue in the treatment of cancer. However, integrating different modes in a system with optimal synergy and minimal side effects remains a challenge. In this study, a multifunctional copper ion-overloaded nanoparticle was fabricated via one-pot self-assembly for enhanced cuproptosis, chemo- and phototherapy. Molecular dynamics simulation was performed to study the self-assembly mechanism, demonstrating they assembled into stable nanoparticles (NPs) in 50 ns. The NPs possess dual-targeting capabilities towards tumor cells and mitochondria, and exhibit excellent stability in neutral PBS, while showing responsive payload release under acidic conditions or NIR laser irradiation. Upon reaching the mitochondria, the NPs release their payloads, where accumulated copper ions trigger aggregation of lipoylated proteins, etc. Released disulfiram chelates excessive copper ion to form toxic Cu(DTC) 2 , which induces apoptosis combining with hydroxycamptothecin. Meanwhile, indocyanine green-generated ROS and photothermal effects further enhance cuproptosis for synergistic therapy. In vitro results revealed potent cytotoxicity of the NPs against CT26 cells while negligible effects on normal cells. Furthermore, significant reactive oxygen species generation, mitochondrial membrane potential alteration, increased apoptosis, and modulated protein mRNA expression levels, confirmed the synergistic combination of chemotherapy, cuproptosis, and photothermal/photodynamic therapies. Notably, in vivo experiments demonstrated selective tumor accumulation and outstanding antitumor efficacy (89.5% inhibition rate) with excellent biosafety profile. The NPs provide a novel strategy for cuproptosis-based combination cancer therapy and shows significant clinical translation potential.

Multifunctional DSF/Cu3BiS3@SS Nanoparticles Loaded with Disulfiram Potentiate Breast Cancer Radiosensitivity by Synergistically Activating Cuproptosis and Apoptosis

Qinyang Lin,Huanhuan Tan,Wenrun Li,Yong Li,Juan Li,Yonghong Ran,Qiuping Wang,Yazhen Zhao,Yuhui Hao

Radiotherapy is an essential method for breast cancer treatment, primarily characterized by directly or indirectly damaging tumor cells. However, owing to the high DNA repair mechanism of tumor cells, the therapeutic efficacy of radiotherapy is frequently affected. To address this dilemma, it is of great significance to develop effective radiosensitizers. Herein, we design DSF/Cu3BiS3@SS nanoparticles (DCBSS NPs) to potentiate radiotherapy efficacy for breast cancer via amplification of cuproptosis and apoptosis. This material exhibits several key features: (1) In the tumor microenvironment, DCBSS NPs have pH-responsive properties. (2) Cu2+ leads to the depletion of glutathione, which facilitates the reduction of Cu2+ to Cu+, collectively inducing intracellular Cu+ overload and triggering cuproptosis. (3) The resultant Cu+ catalyzes Fenton-like reactions, generating abundant reactive oxygen species to intensify oxidative stress. (4) The high-Z (Bi) element can enhance radiation energy deposition, effectively induce DNA damage, and further arrest the cell cycle at the radiosensitive G2/M phase, and Cu2+ reacts with DSF to form CuET, together ultimately amplifying apoptosis. In vivo, DCBSS NPs exhibit effective tumor accumulation via the enhanced permeability and retention effect and achieve an excellent antitumor effect when combined with radiotherapy, with excellent biosafety. This study demonstrates a robust radiosensitization strategy for breast cancer but also introduces an innovative way for cancer therapy based on the regulation of cuproptosis and apoptosis pathways.

Bioinspired zinc-doped carbon dots protect against polystyrene microplastic-induced spermatogenic dysfunction through Nrf2 activation and cuproptosis suppression

Tushuai Li,Kehui Li,Shiqing Yang,Hongying Pan,Zhihui Cai,Xiyao Hua,Guangfu Liao,Bing Luo,Jie Zhang

A zinc-doped trifolirhizin-derived carbon dots was developed. • ZnTFZCDs demonstrate favorable biosafety without overt cytotoxicity, hemolysis, or organ damage. • ZnTFZCDs administration ameliorates testicular histopathology, improves sperm count and morphology. • ZnTFZCDs reactivates the Nrf2/HO-1 antioxidant axis, and suppresses cuproptosis-associated alterations in testicular tissues. Polystyrene microplastics (PS-MPs) are increasingly recognized for their detrimental effects on reproductive health, particularly in the male reproductive system. While mitochondrial oxidative stress is recognized as a driver of MPs-induced reproductive injury, it remains unclear whether this process involves cuproptosis, a newly identified copper-dependent form of regulated cell death, and elucidating this potential link is critical for alleviating such damage. Here, we report that PS-MPs exposure induces testicular injury and spermatogenic dysfunction in mice, associated with redox imbalance, copper transport defects, and upregulation of the cuproptosis regulators Ferredoxin 1 (FDX1) and Lipoic Acid Synthetase (LIAS). In turn, zinc-doped trifolirhizin-derived carbon dots (ZnTFZCDs) were rationally designed via a one-step hydrothermal strategy, embedding the antioxidant properties of a natural flavonoid and the reproductive-protective role of zinc into a biocompatible carbon nanoplatform. ZnTFZCDs are well-dispersed carbon dots rich in oxygen/nitrogen-containing groups with Zn coordination, and demonstrate favorable biosafety without overt cytotoxicity, hemolysis, or organ damage. In vitro , ZnTFZCDs potently scavenge intracellular reactive oxygen species (ROS), maintain antioxidant enzyme activities, preserve mitochondrial membrane potential, suppress lipid peroxidation, and rescue Glutathione peroxidase 4 (GPX4) expression in MPs-exposed RAW264.7 and GC-2 cells. Notably, ZnTFZCDs modulate copper homeostasis by upregulating the copper exporter ATP7B, downregulating the importer SLC31A1, and reducing FDX1/LIAS expression, thereby inhibiting cuproptosis-related signaling. In vivo , ZnTFZCDs administration ameliorates testicular histopathology, improves sperm count and morphology, reactivates the Nrf2/HO-1 antioxidant axis, and suppresses cuproptosis-associated alterations in testicular tissues, confirming the translational potential of the in vitro findings. Collectively, ZnTFZCDs represent a bio-inspired nanoplatform that attenuates PS-MPs-induced male reproductive injury through coordinated modulation of redox and copper homeostasis, offering a new therapeutic strategy for environmental pollutant-related reproductive disorders by targeting the previously overlooked cuproptosis pathway. This work reports a novel zinc-doped trifolirhizin-derived carbon dots (ZnTFZCDs) for attenuating PS-MPs-induced male reproductive injury through coordinated restoration of redox and copper homeostasis. Download: Download high-res image (323KB) Download: Download full-size image

NIR-elicited hydrogel contraction modulates rheological dynamics for spatiotemporally controlled metallo-drug release to potentiate cuproptosis-driven immunotherapy

Wenpei Luo,Lingyun He,Weiwei Liu,Xin Gao,Long Cheng,Min Zheng,Jianli Ren,Haitao Ran,Xun Guo,Lu Yang

Light-responsive control of hydrogel rheology enables precise spatiotemporal drug release. Light-triggered regulation of hydrogel rheology enables spatiotemporally controlled drug release. • Selective copper ion accumulation in tumors induces cuproptosis and synergizes with doxorubicin to promote immunogenic cell death, activating antitumor immunity. • Enhanced dendritic cell maturation and cytotoxic T-cell infiltration effectively convert "cold" tumors into "hot" ones, demonstrating potent antitumor efficacy in mouse models. Activation of cuproptosis has emerged as a paradigm-shifting therapeutic concept to improve cancer immunotherapy efficacy. Nevertheless, its clinical translation is impeded by the inability of existing delivery systems to achieve spatiotemporally precise copper surges within tumor tissues while minimizing systemic metal toxicity. To address this critical issue, we develop a metallo-drug system (HD-HMCS) featuring NIR-triggered and contractility-mediated co-delivery of copper ions and DOX for precisely tumor-localized induction of cuproptosis-immunotherapy. Upon NIR irradiation, the strong photothermal conversion of hollow mesoporous copper sulfide (HMCS) rapidly raises the local temperature to 40 °C, inducing contraction of the PNIPAAm-CS hydrogel shell. The resulting mechanical squeezing force destabilizes the HMCS framework, leading to an instantaneous burst release of the copper-DOX payload. This process induces the downregulation of FDX1 and promotes DLAT oligomerization, thereby enhancing copper-dependent cell death. Furthermore, this approach not only eradicates tumor cells through synergistic cuproptosis and immunogenic cell death (ICD) but also robustly activates systemic antitumor immunity by promoting DC maturation and CD8 + T cell infiltration. Collectively, this work establishes a novel and programmable paradigm for amplifying cuproptosis-immunotherapy, offering a transformative alternative to conventional metal-based nanotherapeutics and a promising synergistic strategy for precision cancer treatment. Download: Download high-res image (77KB) Download: Download full-size image

Engineering of Polymers Decorated Bimetallic Nanoparticles Improves Bacterial Cuproptosis Death in Acute Lung Injury and Pediatric Severe Pneumonia

Xiao Ma,Ge Shi

Pediatric severe pneumonia represents a significant global infectious illness, characterized by elevated morbidity and mortality rates. In light of antibiotic misuse and bacterial biofilm resistance, various metal-based compounds have been established. Nevertheless, the elevated oxygen levels in the lungs enable certain aerobic pathogenic bacteria to exhibit significant tolerance to oxygen and reactive oxygen species (ROS), rendering metal-based materials reliant on ROS potentially ineffective in therapeutic applications. Motivated by the susceptibility to cuproptosis in aerobic respiratory cells, we developed an antibacterial copper nanocomposite. We demonstrated that it can efficiently induce cuproptosis-like mortality in the lungs of aerobic bacteria. To overcome the challenges of in vivo cuproptosis, manganese dioxide was initially used to reduce protective glutathione, which binds copper and thereby prevents its interaction with proteins, thereby facilitating antibacterial action through immunological improvement. Cuproptosis-like cell death necessitates a substantial quantity of copper ions. To satisfy this demand, we provide positively hydrophilic altered CM nanoparticles that efficiently traverse the lung mucus layer via local administration, with copper ions subsequently released rapidly by the acidic conditions at the infection site, thereby enhancing the destruction of bacterial biofilms in conjunction with manganese. This drug-delivery method can efficiently address pediatric severe pneumonia, while mitigating systemic toxicity associated with high dosages of copper.

Targeting ATP7A-Dependent Copper Metabolic Homeostasis Induces Cuproptosis and Suppresses the Progression of Mutant KRAS-Driven Lung Cancer

Zhao Jian,Zhang Weijie,Zeng Yuanyuan,Lu Di,Ma Chenkang,Zhang Mengzhu,Cai Xin,Huang Zhifan,Yang Hongli,Li Jianjun,Zhu Jianjie,Huang Jian-An,Liu Zeyi

Despite progress in tumor-targeted therapy, oncogenic KRAS remains a major challenge in treating lung adenocarcinoma. In clinical practice, KRAS G12C inhibitors have limited response rates and are associated with acquired drug resistance. Cuproptosis is a recently identified form of copper (Cu)-mediated cell death, and previous studies have revealed that Cu metabolism plays an important role in the development of KRAS-driven tumors. In this study, we revealed the therapeutic value of the Cu ionophore elesclomol (ES) for treating KRAS G12 -mutant–driven lung adenocarcinoma. KRAS G12 -mutant lung adenocarcinoma cells relied on the Cu exporter ATP7A to maintain Cu homeostasis. ES induced cellular Cu accumulation and cuproptosis by upregulating the expression of the E3 ligase OSTM1, which interacted with the IRGY motif of ATP7A to promote ubiquitination and degradation. KRAS G12D transgenic mice and lung cancer organoids derived from the mice were used to validate the therapeutic effects of ES and Cu in vivo and in vitro . These findings indicate that KRAS G12 -driven lung adenocarcinoma relies on ATP7A-mediated Cu metabolic homeostasis, which can be perturbed with ES as an effective treatment strategy. Significance: The copper ionophore elesclomol is effective for treating KRAS-driven lung cancer by activating the OSTM1-ATP7A regulatory axis to perturb copper metabolism homeostasis.

Targeted modulation of dual-metal ion homeostasis to induce ER stress and cuproptosis for synergistic breast tumor suppression

Xiaoxian Zhang,Xuequan Zhang,Jiahui Zhu,Tinghua Li,Lianyi Yang,Lei Lei,Fang Wu,Bin He,Jun Cao

Targeted modulation of metal ion homeostasis in tumor cells has emerged as a promising method for cancer therapy. However, the coordination efficiency and stability of different metal ions posed significant challenges for current multi-metal ions delivery systems. In this study, we presented an innovative strategy that utilized a single-metal ion nanoregulator capable of precisely modulating intracellular dual-metal ions homeostasis. This regulation induced endoplasmic reticulum (ER) stress and cuproptosis, which worked synergistically to inhibit tumor growth. Specifically, a calcium-selective chelator, BAPTA, formed a metal coordination complex with copper ions (Cu 2+ ), which remained stable in the extracellular environment but disassembled upon internalized by tumor cells. Once inside, the released BA selectively chelated cytoplasmic calcium ions (Ca 2+ ), depleting ER Ca 2+ stores and triggering ER stress. This stress activated the PERK/p-eIF2α/ATF4/CHOP apoptotic pathway, leading to tumor cell apoptosis. Meanwhile, Cu 2+ induced cuproptosis and was reduced to Cu + in the cytosol, where it consumed hydrogen peroxide and generated cytotoxic hydroxyl radicals. These radicals induced oxidative stress, which, combined with glutathione depletion, further amplified ER stress and promoted tumor cell apoptosis. Both in vitro and in vivo experiments exhibited that the nanoregulator effectively suppressed tumor growth through apoptosis and cuproptosis pathways, with favorable biocompatibility. This study highlighted the synergistic roles of copper and calcium ions in tumor therapy and introduced a novel strategy for modulating intracellular dual-metal ions homeostasis, offering more efficient and low toxicity anti-cancer treatments.

A Tumor Microenvironment-responsive Nanocomposite for Enhanced Copper Retention and Hypoxia Reversal to Promote Cuproptosis in Tumor Treatment

Wei Chen,Chen Lin,Zhimin Gao,Yongxin Huang,Xinyi Wang,Qian Zhang,Yaru Zhang,Meiling Tan,Zhiyao Hou

Copper (Cu) ions are essential for inducing cuproptosis to inhibit tumor growth, and the therapeutic efficacy is limited by the chelation of over-expressed glutathione (GSH) and the efflux mechanisms of copper transporter proteins. Moreover, the hypoxic characteristic of the tumor microenvironment (TME) can impede the formation of lipoylated proteins in the tricarboxylic acid (TCA) cycle, thereby diminishing cuproptosis. Herein, Cu 2 O was served as active nano-carrier for delivering copper, followed by coating with cerium-based node metal-organic frameworks (Ce-MOFs) in situ on the surface to form core-shell structure Cu 2 O@Ce-MOFs (CM). Subsequently, the small molecule glucose transporter (GLUT) inhibitor KL-11743 was loaded onto CM to construct Cu 2 O@Ce-MOFs/KL-11743 (CMK) nanocomposites, achieving efficient cuproptosis for tumor treatment. The results show that CMK regulated the redox metabolism of the tumor microenvironment (TME) through glutathione oxidase (GSHOx) and peroxidase (POD) activities, significantly consuming excessive GSH and preventing copper ions from being chelated. Furthermore, KL-11743 released in response to TME inhibited the transport of glucose into cells via GLUT, resulting in a reduction of ATP synthesis and down-regulation of ATP7B expression, thereby achieving the restriction of copper ion efflux by regulating energy metabolism. The catalase (CAT) activity of CMK catalyzed the overexpressed H 2 O 2 in TME to generate O 2 , which entered the TCA cycle to promote lipoylated proteins oligomerization for sensitizing cuproptosis. Summary, CMK nanocomposites increased the effective Cu ions concentration within tumor cells by regulating metabolism, resulting in toxicity stress by hypoxia reversion induced efficient cuproptosis, which provides a potential strategy for clinical tumor treatment. Statement of significance This study addresses the challenge of insufficient effective copper ions and hypoxia in inhibiting cuproptosis by constructing TME-responsive Cu₂O@Ce-MOFs/KL-11743 (CMK) nanocomposites. In this design, CMK enhances intracellular copper retention through dual mechanisms: (1) redox metabolic regulation-mediated GSH depletion to inhibit copper ion chelation, and (2) KL-11743-targeted suppression of copper efflux via energy metabolic pathway inhibition. Concurrently, the enzyme-mimic activity of CMK catalyzes overexpressed H₂O₂ in the TME into O₂, alleviating hypoxia to promote lipoylated protein oligomerization. The synergistic integration of metabolic modulation and hypoxia reversal enables robust cuproptosis induction, establishing a reliable and clinically viable strategy for tumor treatment.