Table 3 Nanomedicines targeting cuproptosis for cancer treatment
From: Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives
Nanomedicine | Components | Cancer type | Materias (cell lines) | Type of dynamic therapy | Combined drugs | Function description | Refs. |
|---|---|---|---|---|---|---|---|
GOx@[Cu(tz)] | GOx, Cu2O, 1,2,4-triazole | Bladder cancer | 5637 tumor | PDT | GOx@[Cu(tz)] induces cuproptosis in cancer cells under conditions of glucose depletion and suppresses tumor growth of 5637 bladder tumorsin in athymic | [164] | |
Cu2(PO4)(OH) NPs | Cu2(PO4)(OH) | CRC | HCT116 tumor | Cu2(PO4)(OH) NPs can induce pyroptosis by ROS-mediated Caspase 1 activation and gasdermin D cleavage, and efficiently induce cuproptosis by downregulating ATP7A to maximizing Cu overload | [165] | ||
DSF@PEG/Cu-HMSNs | Disulfiram, PEG, Cu2+, HMSNs | Breast cancer | 4T1 tumor | PTT | DSF@PEG/Cu-HMSNs can induce toxic mitochondrial protein aggregation, leading to cell cuproptosis | [166] | |
HFn-Cu-REGO NPs | Human heavy chain ferritin, Cu2+, regorafenib | GBM | U251, U87 tumor | regorafenib | HFn-Cu-REGO NPs could result in lethal autophagy arrest in GBM cells via releasing regorafenib that can inhibit autophagosome-lysosome fusion, and disturbs copper homeostasis for triggering cuproptosis by releasing Cu2+ | [167] | |
Cu-GA NPs | Cu2+, Gallic acid, polyvinylpyrrolidone | Breast cancer | 4T1 tumor | CDT | Cu-GA NPs can induce severe cell cuproptosis and apoptosis by depleting intracellullar GSH ad generating ROS, and effectively suppress tumor growth when combining with CDT | [168] | |
Au@MSN-Cu/PEG/DSF | Au nanorods, Cu(NO3)2, PEG, disulfiram | Breast cancer | 4T1 tumor | PTT | In synergy with PTT, Au@MSN-Cu/PEG/DSF could effectively kill tumor cells and inhibit tumor growth by inducing the cell apoptosis and cuproptosis | [169] | |
DMMA@Cu2−xSe | Poly(ethylene imine), 2,3-dimethylmaleic anhydride, Cu2−xSe, RGD polypeptide | Melanoma | A375 tumor | PTT | DMMA@Cu2−xSe can induce cuproptosis by releasing Cu2+, which further improves thermotherapy by up-regulating mitochondrial damage-meidated ROS. DMMA@Cu2−xSe combined with laser has a satisfactory antitumor effect in melanoma tumor-bearing nude mice | [170] | |
NP@ESCu | Amphiphilic biodegradable polymer, elesclomol–Cu | Bladder cancer | MB49 tumor | αPD-L1 | NP@ESCu could induce tumor cell cuproptosis and reprograme TME. Combined with αPD-L1, NP@ESCu can efficiently suppress tumor growth in mouse models with subcutaneous bladder cancer | [171] | |
HNP | DTPH, Cu2+, disulfiram, hyaluronan, artemisinin | Breast cancer | 4T1 tumor | HNP could deplete GSH by riched disulfide bonds to sensitize cancer cells to the cuproptosis. HNP can effectively suppress tumor growth by a synergistic combination of cuproptosis, ferroptosis, and apoptosis | [172] | ||
CS/MTO-Cu@AMI | Mitoxantrone, Cu2+, amiloride, chondroitin sulfate | Breast cancer | 4T1 tumor | CS/MTO-Cu@AMI induces cuproptosis and mitochondrial damage, which actviates the AMPK pathway to orchestrate PD-L1 degradation. CS/MTO-Cu@AMI could induce anti-tumor immunity by activating the cGAS-STING pathway | [173] | ||
CCJD-FA | CaO2, Cu2+, DTPH, DSPE-PEG-FA, JQ-1 | CRC | CT26 tumor | JQ-1 | CCJD-FA could induce severe cuproptosis by releasing Cu and inhibiting intracellular glycolysis and ATP production, and reduce the expression of IFN-γ-induced PD-L1 by suppressing BRD4. These effects make cancer cells more susceptible to cuproptosis and reshape immunosuppressive TME to inhibit tumor growth | [174] | |
CuET NPs | BSA, CuET, NaDTC | Lung cancer | A549 tumor | CuET NPs can suppress the growth of cisplatin-resistant tumor cells in vitro and in vivo with superior biosafety | [175] | ||
BSO-CAT@MOF-199 @DDM (BCMD) | BSO, DDM, Cu-based MOF of MOF-199 | GBM | GL261 tumor | αPD-L1 | BCMD could induce tumor cell cuproptpsis, which triggers ICD and enhances tumoricidal immunity. Combining with αPD-L1, BCMD could further cooperate to reconstruct the TIME and enhance the therapeutic effect | [176] | |
CuMoO4 Nanodots | Cu2+, MoO42−, SDS | Breast cancer | MCF-7, 4T1 tumor | PTT | Under sustained PTT, CuMoO4 Nanodots can effectively induce ferroptosis and cuproptosis in tumor cells and trigger an immune response to ICD | [177] | |
TP-M–Cu–MOF/siATP7a | Cu–MOF, siATP7a, TPM | HSCLC | H69 tumor | TP-M–Cu–MOF/siATP7a presents high blood–brain barrier transcytosis and specific uptake by tumor cells within the brain, and exhibits high silencing efficiency against ATP7A to increasing copper intake, thereby inducing cuproptosis and enhancing therapeutic efficacy in HSCLC brain metastasis tumor-bearing mice | [178] | ||
SonoCu | Cu2+, zeolitic imidazolate framework-8, perfluorocarbon, chlorin e6, O2 | Breast cancer | 4T1 tumor | SDT | Combining with SDT, SonoCu can induce tumor cell cuproptosis but sparing normal cells. SonoCu provides a desirable antitumor outcome with good biosafety | [179] | |
Au NCs-Cu2+@SA-HA NHGs | NAC, 4-mercaptobenzoic acid, HAuCl4, NaOH, NaBH4, CuCl2, | HCC | HepG2, H22 tumor | PTT, PDT | Au NCs-Cu2+@SA-HA NHGs can respond to NIR, enhancing PTT and PDT. The release of Cu2+ triggers cuproptosis, catalyzes H2O2 to generate O2, and consumes GSH to form hydroxyl radicals, synergistically improving PDT and CDT | [180] | |
CuX-P | PD-1 overexpressing T cell membrane, Mxene, Cu2+, disulfiram | Breast cancer | 4T1 tumor | PTT | CuX-P can bind to PD-L1 on tumor cells, leading to internalization and upregulation of PD-L1 expression. The feedback loop between CuX-P and PD-L1 promotes PD-L1 consumption and CuX-P enrichment in tumors, inducing cuproptosis. Laser treatment with CuX-P stimulates potent anti-tumor immune responses | [181] | |
Cu2O@CuBTC-DSF@HA nanocomposites (CCDHs) | Cu2O, Trimesic acid, disulfiram, Hyaluronic acid | Breast cancer | 4T1 tumor | CCDHs synergistically enhance cuproptosis instead of inducing apoptosis, demonstrating superior anti-tumor efficacy with minimal toxicity | [182] | ||
Cu-LDH | Layered double hydroxide, Cu2+ | Breast cancer | 4T1 tumor | Cu-LDH nanoparticles function as lysosome destroyers, enhancing Cu overload-mediated cuproptosis and pyroptosis for efficient cancer immunotherapy | [183] | ||
PCM nanoinducers | PEG-polyphenol-Ce6 polymer; Cu2+; Mdivi-1; | Breast cancer | 4T1 tumor | Mdivi-1 | PCM nanoinducers amplify proteotoxic stress through cuproptosis and cause mtDNA release, activating the cGAS-STING pathway. This activation triggers both innate and adaptive immune responses, effectively combating tumor growth and systemic metastasis | [184] | |
Cu-DBCO/CL | Cu-DBCO; CHO; LOX-IN-3; 2,2′-PSDA | Breast cancer | 4T1 tumor | Cu-DBCO/CL induces tumor cell cuproptosis and ferroptosis, simultaneously enhancing ICD and remodeling the ECM, resulting in significant tumor growth and metastasis inhibition | [185] | ||
OMP | OPDEA, 2-methylimidazole, Cu(NO3)2, Zn(NO3)2·6H2O, siPDK | Melanoma | Mice-bearing B16F10 lung melanoma metastasis | aPD-L1 | OMP induces tumor cells cuproptosis. siPDK released from OMP sensitizes the cuproptosis by inhibiting intracellular glycolysis and ATP production, and blocking the Cu+ efflux protein ATP7B. OMP-mediated cuproptosis triggers ICD to promote DCs maturation and CD8+ T cells infiltration, and upregulates membrane-associated PD-L1 expression, offering improved efficacy against lung metastasis when combined with aPD-L1 | [186] | |
M@HMnO2-DP | HMnO2, disulfiram, Prodrugs 4 and 5, 4T1 cancer cell membrane | Breast cancer | 4T1 tumor | M@HMnO2-DP specifically targets cancer cells to deliver disulfiram, triggering cuproptosis without exogenous Cu. This compound inhibits tumor cell glycolysis through bioorthogonal chemistry-based drug synthesis and disrupts Fe–S protein biosynthesis, enhancing cuproptosis sensitivity | [187] | ||
PDA-DTC/Cu NPs | Diethyldithiocarbamate, Polydopamine, Cu2+ | Breast cancer | 4T1 tumor | PDA-DTC/Cu NPs induce the tumor cell cuproptosis by elevating intracellular Cu accumulation, disrupting mitochondrial function, and restricting the ATP energy supply, promoting the repolarization of TAMs to relieve the TIME | [188] | ||
HA-CD@MOF NPs | Cu2+, DOX, hyaluronate acid | Breast cancer | 4T1 tumor | CDT | DOX | Combining chemodynamic therapy with Cu2+ overload exacerbates ROS storms and mitochondrial damage, sensitizing cuproptosis. HA-CD@MOF NPs robustly activate ICD and suppress tumor metastasis | [189] |
MCD | MSN, Cu2S; oxidized dextran | Osteosarcoma | [143B tumor | PTT | MCD triggers tumor cell cuproptosis by inhibiting key TCA cycle proteins, showing promising mild-temperature PTT in the NIR-II range, effectively reducing tumor growth and OS-induced bone destruction in vivo | [190] | |
CDPh | DMONs, Cu, phloretin | CRC | CT26 tumor | PTT | In-situ activation of CDph facilitates Cu dissociation and glutathione consumption, triggering cuproptosis. The ROS storm generated by mild photothermal-enhanced peroxidase (POD)-like reaction and glycolysis interference by glucose transporter inhibitor phloretin (Ph) synergistically disrupts cellular Cu homeostasis, leading to cancer cell cuproptosis | [191] | |
CuET@PH NPs | polydopamine; hydroxyethyl starch; CuET | PDAC | Panc02 tumor | HBO | HBO and CuET@PH NPs inhibit glycolysis and oxidative phosphorylation, respectively, suppressing cancer stem cell energy metabolism, achieving robust tumor inhibition in PDAC and significantly extending mouse survival | [192] | |
CuO2/DDP@SiO2 | CuO2; DDP; SiO2 | HCC | H22 tumor | CDT | Cisplatin | CuO2 generates O2, increases pH, and oxidizes intracellular GSH, sensitizing cancer cells to CuO2/DDP@SiO2-mediated cuproptosis. CuO2 significantly downregulates multidrug resistance-associated protein 2 through O2-dependent HIF-1 inactivation, blocking the cisplatin-efflux pathway and enhancing cisplatin's antitumor effects | [193] |
Cu/APH-M | HPB, Au–Pt nanozymes, Cu2+, cancer cell membrane; | CRC | CT26 tumor | αPD-L1 | Cu/APH-M effectively carries Cu and induces cuproptosis in tumor cells. Cu/APH-M also can enhance the oxygenation of the TME to trigger robust antitumor immunity, and synergize with immunotherapy to prevent distant tumor recurrence, particularly in low rectal cancer | [194] | |
PCD@CM | NIR-II ultrasmall polymer dots; Cu2+; DOX; 4T1 cell membrane | Breast cancer | 4T1 tumor | DOX, aPD-L1 | PCD@CM induces the aggregation of lipoylated mitochondrial proteins and the loss of iron-sulfur proteins, leading to severe proteotoxic stress and ultimately cuproptosis. NIR-II PTT and GSH depletion render tumor cells more sensitive to cuproptosis. The amplified cuproptosis triggers ICD to promote cytotoxic T lymphocyte infiltration along with aPD-L1-mediated immune checkpoint blockade | [195] | |
ES@CuO | CuO; elesclomol; glycol polymer | Melanoma | B16 tumor | αPD-1 | ES@CuO synergistically triggers tumor cell cuproptosis, promotes cuproptosis-mediated immune responses, and increases the number of tumor-infiltrating lymphocytes and secreted inflammatory cytokines. Combining ES@CuO with PD-1 immunotherapy substantially increases antitumor efficacy in murine melanoma | [196] | |
D-CuxOS@Fe–MOF | Cu2+; Fe3+; D-/L-penicillamine; NH2-BDC | Breast cancer | 4T1 tumor | D-CuxOS@Fe–MOF induces augmented oxidative stress and potent ferroptosis, synergizing with cuproptosis for enhanced cancer therapy | [197] | ||
ES-Cu-Alg hydrogel | Cu2+; elesclomol; sodium alginate; galactose | CRC | CT26 tumor | Elesclomol–Cu–Alg hydrogel effectively induces cuproptosis in colorectal cancer cells, abrogates radiation-induced PD-L1 upregulation, and sensitizes tumor cells to radiotherapy and immunotherapy | [198] | ||
T-HCN@CuMS | HCN, CuMS, cRGDfk-PEG2k-DSPE | Osteosarcoma | [143B tumor | PTT | T-HCN@CuMS demonstrates favorable photo-induced catalytic properties, generating abundant ROS under NIR light irradiation. It efficiently catalyzes the Fenton-like reaction, triggering cell cuproptosis and achieving favorable therapeutic outcomes to inhibit tumor growth and metastasis | [199] | |
CJS-Cu NPs | BETA, Cu+ | Breast cancer | 4T1 tumor | PTT | CJS-Cu NPs selectively induce cuproptosis and downregulate metastasis-related protein expression, contributing to the complete inhibition of lung metastasis | [200] | |
CQG NPs | Cu2+; Polyvinylpyrrolidone, Gallic acid; (3-aminopropyl) triethoxysilane, GOx | Breast cancer | 4T1 tumor | CQG NPs induce cuproptosis by releasing Cu and depleting endogenous Cu chelators, disrupting the antioxidant defense mechanism of tumor cells. This promotes immunosuppressive TME remodeling, enhances immune cell infiltration into the tumor, and activates robust systemic immunity | [201] | ||
Cu2O@Mn3Cu3O8 (CMCO) nanozyme | Cu2O; Mn3Cu3O8 | CRC | CT26 tumor | PTT | CMCO nanozyme induces high-efficiency ferroptosis-boosted cuproptosis via a mild-photothermal effect for colorectal cancer therapy | [202] | |
Cu-doped BiSex (CBS) | CuI; Bi2Se3 | PC-3 tumor | PTT | αPD-L1 | CBS induces cuproptosis and apoptosis through photothermal effects and augmented oxidative stress, boosting antitumor immune responses when combined with αPD-L1 | [203] | |
E-C@DOX NPs | Cu2+; ellagic acid, DOX, chondroitin sulfate | Breast cancer | 4T1 tumor; MCF7Adr tumor | DOX | E-C@DOX NPs inhibit tumor cell stemness and cell survival-related pathways while working in tandem with Cu to damage mitochondria and induce cuproptosis. This suppresses the ATP-dependent drug efflux pathway, reversing DOX resistance | [204] | |
E. coli@Cu2O | E. coli; Cu2O | Colon tumor | MC 38 tumor | PTT | αPD-1 | E. coli@Cu2O induces cellular ferroptosis and cuproptosis. Photothermal-enhanced ferroptosis/cuproptosis reverses the immunosuppression of colon tumors by triggering DC maturation and T cell activation | [205] |
Cu@CDCN | Cu2+, carbon photocatalyst | Breast cancer | 4T1 tumor | PTT | Cu@CDCN, with efficient photocatalytic H2 production and anchored Cu2+, enables a combination of hydrogen therapy and cuproptosis, causing mitochondrial damage and inhibiting tumor growth | [206] | |
LDH/HA/5-FU nanosheets | 5-FU; copper–aluminum layered double hydroxide, hyaluronic acid | Breast cancer | 4T1 tumor | CDT | 5-FU | LDH/HA/5-FU nanosheets specifically target tumor cells, rapidly release Cu2+ and 5-FU, and induce tumor cell apoptosis and cuproptosis. These nanosheets successfully promote the immune system, combining Cu-based CDT and chemotherapy, showing promising potential for solid tumor treatments | [207] |
PEG@Cu2O-ES | Cu2O; Elesclomol; PEG | Breast cancer | 4T1 tumor | PTT, CDT | αPD-1 | PEG@Cu2O-ES, with PTT and CDT effects, generates ROS to attack the ATP-Cu pump, reducing Cu ion outflow and aggravating cuproptosis. PEG@Cu2O-ES shows strong antitumor effects by inducing cuproptosis, reprogramming TME, and increasing response sensitivity to αPD-1 | [208] |
CCNAs | ZnPc; thioketal, 1-MT; DOX; Cu2+ | Prostate cancer | PC-3 tumor | PTT | DOX | Upon NIR laser irradiation, ZnPc exhibits a photodynamic effect generating ROS, triggering DOX release, and enhancing tumor cell apoptosis. Cu2+ in the CCNAs enhances the photodynamic process, promoting toxic mitochondrial protein aggregation and leading to cell cuproptosis. This intensified cuproptosis-apoptosis effect triggers an ICD response, and released 1-MT reverses ITM by suppressing IDO-1-mediated Trp degradation | [209] |
ZCProP | Zeolitic imidazole framework-90, Cu2+; prodigiosin, PEG | Breast cancer | 4T1 tumor | ZCProP delivers Cu and prodigiosin to mitochondria, inducing cell death through synergistic mechanisms of cuproptosis, ferroptosis, and apoptosis | [210] | ||
MetaCell | Fe3+; Cu2+; 2-Aminoterephthalic acid, thermosensitive liposome | Breast cancer | 4T1 tumor | PTT | MetaCell effectively evades the immune system, penetrates tumors, and maintains stability under various conditions. MetaCell instigates cuproptosis and ferroptosis, resulting in substantial efficacy against cancer cells in vitro and in vivo | [211] | |
ECPCP | Elesclomol–Cu, cinnamaldehyde, polyethylene glycol | Breast cancer | 4T1 tumor | ECPCP significantly prolongs the systemic circulation of elesclomol–Cu, enhances tumor accumulation, and induces cuproptosis. Cu2+-stimulated Fenton-like reactions and cinnamaldehyde-stimulated ROS production simultaneously break redox homeostasis, inducing ICD of tumor cells and achieving cuproptosis and immunotherapy | [212] | ||
CLDCu | Cu2+, disulfiram, LMWH-TOS, chitosan | Melanoma | B16F10 tumor | aPD-L1 | CLDCu induces cuproptosis by releasing Cu2+ and disulfiram and activates the STING pathway by releasing chitosan, potentiating DC maturation and evoking innate and adaptive immunity. CLDCu combined with aPD-L1 provokes stronger antitumor immunity | [213] | |
DCM@GDY-CuMOF@DOX | graphdiyne, CuMOF, DOX, DU145 cell membrane | Prostate cancer | DU145 cell tumor | DOX | DCM@GDY-CuMOF@DOX exhibits remarkable cell-killing efficiency by generating lethal ROS and mediating cuproptosis, effectively suppressing tumor growth in vivo without causing apparent side effects | [214] | |
O2-PFH@CHPI NPs | Cu2+; indocyanine green; O2-saturated perfluorohexane | HCC | Huh7 tumor | PTT | Upon NIR, O2-PFH@CHPI NPs accelerate catalytic reactions, trigger O2 release for PDT, promote oxidative stress, and effectively activate through Cu+-mediated cuproptosis. The redox balance tilt promotes lipid peroxidation and GPX4 inactivation, resulting in augmented ferroptosis | [215] | |
PCB | Cu-doped polypyrrole nanoparticles BPTES, platelet membrane | Breast cancer | 4T1 tumor | PCB amplifies oxidative stress and induces DLAT oligomerization by releasing CuP, resulting in cuproptosis, which is enhanced by GLS1 inhibitor BPTES. PCB induces ICD, promoting immune cell infiltration into the tumor | [216] |