Table 3 Cuproptosis-associated nano-drug delivery systems

GOx@(Cu(tz))

Glucose oxidase (GOx), Cu₂O, 1,2,4-triazole (Htz)

Glucose depletion and GSH stimulation

GOx@(Cu(tz)) can induce cuproptosis in cancer cells under conditions of glucose depletion. Furthermore, GOx@(Cu(tz)) effectively inhibited tumor growth in athymic mice bearing 5637 bladder tumors

[205]

DSF@PEG/Cu-HMSNs

DSF, PEG, Cu²⁺, hollow mesoporous silica nanoparticles (HMSNs)

Mild acidic TME

This nanosystem effectively curbed the growth of 4T1 cell-derived tumors in female BALB/C nude mice

[206]

E-C@DOX NPs

Cu²⁺; ellagic acid (EA); DOX; chondroitin sulfate (CS)

GSH; low-pH environment; CS-mediated internalization

E-C@DOX NPs inhibits tumor cell stemness and cell survival-related pathways, while working in tandem with Cu ions to damage mitochondria and induce cuproptosis, thereby suppressing the ATP-dependent drug efflux pathway and reversing DOX resistance

[207]

LDH/HA/5-FU nanosheets

5-FU; copper–aluminum layered double hydroxide (CuAl-LDH); hyaluronic acid (HA)

pH-responsive; CD44-targeting property of HA

LDH/HA/5-FU nanosheets could rapidly release Cu (II) and 5-FU in tumor cells, and induce tumor cell apoptosis and cuproptosis. LDH/HA/5-FU nanosheets show excellent inhibitory effects on tumors by combining Cu-based chemical dynamics therapy (CDT) and chemotherapy

[208]

PTC

Cu₂O, AIE photosensitizer (TBP-2), Platelet vesicle (PV),

Acid conditions and hydrogen peroxides; light irradiation

PTC therapy can specifically induce cuproptosis in tumor cells, significantly suppressing the lung metastasis of breast cancer, increasing the population of central memory T cells in peripheral blood, and preventing tumor recurrence

[211]

Au@MSN-Cu/PEG/DSF

Au nanorods (NRs), Cu(NO₃)₂, PEG, DSF

PTT

Au@MSN Cu/PEG/DSF can effectively induce tumor cell death and suppress tumor growth in synergy with PTT

[212]

O₂-PFH@CHPI NPs

Cu²⁺; indocyanine green; O₂-saturated perfluorohexane (PFH)

pH-Responsive; PTT

Upon NIR, O₂-PFH@CHPI NPs can simultaneously accelerate catalytic reactions, trigger O² release for PDT to promote oxidative stress, and effectively activate Cu⁺-mediated cuproptosis. Moreover, the tilt of redox balance promotes lipid peroxidation and GPX4 inactivation, resulting in an augmented ferroptosis

[213]

NP@ESCu

Amphiphilic biodegradable polymer (PHPM), ES-Cu

Excessive intracellular ROS

When combined with αPD-L1, NP@ESCu could induce cuproptosis, which enhances the effectiveness of cancer treatment in mouse models with subcutaneous bladder cancer

[214]

CS/MTO-Cu@AMI

Mitoxantrone (MTO), Cu²⁺, amiloride (AMI), chondroitin sulfate (CS),

CS guided CD44 receptor-mediated tumor-specific target; pH/GSH dual-responsive delivery behavior

CS/MTO-Cu@AMI activated the AMPK pathway by inducing cuproptosis and mitochondrial dysfunction, orchestrating the degradation of PD-L1. The treatment-induced dsDNA damage stimulated antitumor immunity through the activation of the cGAS–STING pathway

[215]

CCJD-FA

CaO₂, Cu²⁺, 3,3′-dithiobis(propionohydrazide) (DTPH), DSPE-PEG-FA, JQ-1

GSH; the acidic condition

CCJD-FA inhibited intracellular glycolysis and ATP production and reduced the expression of IFN-γ-induced PD-L1. This made cancer cells more susceptible to cuproptosis and enhanced immune responses to inhibit tumor growth

[216]

BSO-CAT@MOF-199 @DDM (BCMD)

Butythione sulfoxideimine (BSO), catalase (CAT), dodecyl-β-d-maltoside (DDM), Cu-based MOF of MOF-199

Slightly acidic tumor environment

BCMD-induced cuproptosis of glioblastoma, which in turn triggers immunogenic cell death (ICD) and enhances tumoricidal immunity. Combined with αPD-L1, BCMD substantially enhances the antitumor therapeutic efficiency of immune checkpoint blockade therapy

[217]

Cu-doped BiSex (CBS)

CuI; Bi₂Se₃;

PTT

CBS induces cuproptosis and apoptosis and boosts antitumor immune responses during combining with αPD-L1

[218]

CLDCu

Cu²⁺; DSF; low molecular weight heparin-tocopherol succinate (LMWH-TOS); chitosan

Mildly acidic pH condition

CLDCu can trigger enhanced cuproptosis by releasing Cu²⁺ and DSF, and activate STING pathway by releasing chitosan, which potentiates dendritic cells (DCs) maturation and evokes innate and adaptive immunity. CLDCu combined with PD-L1 provokes stronger antitumor immunity

[219]

PEG@Cu₂O-ES

Cu₂O; ES; PEG;

PTT/CDT

PEG@Cu₂O-ES with PTT and CDT effects could generate ROS to attack the ATP-Cu pump, thereby reducing the outflow of Cu ions and aggravating cuproptosis. PEG@Cu₂O-ES showed strong antitumor effect by inducing cuproptosis, reprogramming TME and thus increasing the response sensitivity to αPD-1

[220]

CuMoO₄ Nanodots

Cu²⁺, MoO₄²⁻, SDS

PTT

Under sustained PTT, CuMoO₄ can effectively induce both cuproptosis and ferroptosis in tumor cells, thereby triggering an immune response to ICD

[221]

CSTD-Cu(II)@DSF

Generation 5 (G5), phenylboronic acid (PBA), mannose, Cu²⁺, DSF

Low pH; high ROS

CSTD-Cu (II)@DSF showed significant potential in suppressing the growth of MCF7 tumors by integrating chemotherapy with cuproptosis and CDT. Moreover, it allows for T1-weighted real-time MR imaging of tumors in vivo

[222]

Au NCs-Cu²⁺@SA-HA NHGs

NAC, 4-mercaptobenzoic acid (4-MBA), HAuCl₄, NaOH, NaBH₄, CuCl₂,

Excessive existence of H⁺ ions; PTT; PDT

The use of Au25(NAMB)18 NCs-Cu²⁺@SA/HA NHGs can significantly enhance the efficacy of cuproptosis-based tumor therapy by depleting the overexpressed GSH and H₂O₂ in the TME. Simultaneously, Au25(NAMB)18 NCs-Cu²⁺@SA/HA can be employed for imaging-guided diagnosis and treatment of tumors

[223]

Cu2O@CuBTC-DSF@HA nanocomposites (CCDHs)

Cu₂O, trimesic acid (H₃BTC), DSF, hyaluronic acid (HA)

Acidic environment

CCDHs synergistically enhanced cuproptosis rather than trigger apoptosis, exhibiting superior anti-tumor effectiveness and minimal toxicity

[224]

SonoCu

Cu²⁺, zeolitic imidazolate framework-8, perfluorocarbon (PFC), chlorin e6 (Ce6), O₂

Sonodynamic therapy

SonoCu activated sonodynamic cuproptosis, showing cytotoxicity against cancer cells but sparing normal cells in response to ultrasound treatment

[225]

CuX-P

PD-1-overexpressing T cell membrane, Mxene, Cu²⁺, DSF

PD-1

CuX-P can bind with and deplete PD-L1 on the surface of tumor cells, promoting its endocytosis. This action may trigger cuproptosis in tumor cells, thereby intensifying the antitumor immune responses in TNBC

[226]

DMMA@Cu₂-xSe

Poly(ethylene imine) (PEI), 2,3-dimethylmaleic anhydride (DMMA), Cu₂-xSe, RGD polypeptide

The weak, acidic environment

DMMA@Cu₂-xSe displayed the ability to enhance thermotherapy through cuproptosis-driven mechanisms

[227]

ART@CuT/ETH HNP

3,3′-Dithiobis(propionohydrazide) (TPH), Cu²⁺, DSF, hyaluronan (HAT), artemisinin (ART)

Acidic and GSH-rich intracellular microenvironment

ART@CuT/ETH HNP effectively triggered cancer cell death through a synergistic combination of cuproptosis, apoptosis, and ferroptosis

[228]

ZIF-8-Cu₂O-DNA

ZIF-8, Zn²⁺, Cu₂O, DNA

The weak, acidic environment

ZIF-8-Cu₂O-DNA was able to increase ROS and enhance cuproptosis, thereby inhibiting tumor growth by synergizing cuproptosis with genic and CDT

[229]

CuET NPs

Bovine serum albumin (BSA), CuET, sodium diethyldithiocarbamate trihydrate (NaDTC)

Not described

CuET NPs notably induced cuproptosis in A549/DDP cells and effectively inhibited tumor growth in a cisplatin-resistant tumor model, demonstrating superior biosafety

[230]

TP-M–Cu–MOF/siATP7a

Copper-based metal–organic frameworks (Cu-MOF), siRNA targeting ATP7a (siATP7a), TP0751 peptide appended stem cell membrane (TPM)

TP0751 peptide decorated mesenchymal stem cell membrane

TP-M–Cu–MOF/siATP7a efficiently silenced the ATP7A gene and increased copper intake, thereby inducing cuproptosis and enhancing therapeutic efficacy in small-cell lung cancer brain metastasis tumor-bearing mice

[231]

Cu-GA NPs

Cu²⁺, gallic acid (GA), polyvinylpyrrolidone (PVP)

Highly expressed GSH in tumor cells

Cu-GA NPs significantly depleted intracellular GSH and increased ROS levels, resulting in severe cell cuproptosis and apoptosis. In vivo experiments demonstrated that Cu-GA NPs effectively suppressed tumor growth through a combination of chemotherapy and CDT

[232]

HFn-Cu-REGO NPs

Human heavy-chain ferritin (HFn), Cu²⁺, Regorafenib

HFn guided GBM accumulation; pH-responsive delivery behavior

HFn-Cu-REGO NPs exhibited excellent GBM suppression in vivo due to their ability to block autophagic flux and induce cuproptosis

[233]

Cu₂(PO₄)(OH) NPs

Cu₂(PO₄)(OH)

H₂S-induced copper overload in tumor TME

Cu₂(PO₄)(OH) NPs inhibited tumor cell growth by triggering cuproptosis and pyroptosis

[234]

Cu-LDH

Layered double hydroxide (LDH) nanoparticle; Cu²⁺

Tumor site injection; acidic condition responsive

Cu-LDH nanoparticles, as lysosome destroyer, enhance Cu-mediated cuproptosis and pyroptosis for high-efficiency cancer immunotherapy

[235]

Cu-DBCO/CL

Cu-dibenzo-[g,p]chrysene-2,3,6,7,10,11,14,15-octaol (DBCO); cholesterol oxidase (CHO); lysyl oxidase inhibitor (LOX-IN-3); 2,2′-[propane-2,2-diylbis(thio)]diacetic acid linker (PSDA)

ROS-responsive

Cu-DBCO/CL triggers tumor cell cuproptosis and ferroptosis, simultaneously enhances ICD of cancer cells and reinvents the ECM, leading to a potent inhibition of tumor growth and metastasis

[236]

OMP

2-(N-oxide-N,N-diethylamino)ethyl methacrylate (OPDEA); 2-methylimidazole; Cu(NO₊)₂; Zn(NO3)₂⋅6H₂O; siPDK

OPDEA-mediated pulmonary mucosa penetration

siPDK released from OMP sensitizes the cuproptosis by inhibiting intracellular glycolysis, ATP production, and blocking the Cu⁺ efflux protein ATP7B. OMP-mediated cuproptosis triggers ICD to promote DC maturation and CD8⁺ T cells infiltration, upregulates membrane-associated PD-L1 expression and induces soluble PD-L1 secretion. OMP combined with aPD-L1 afford preferable efficacy against lung metastasis

[237]

MCD

Dendritic mesoporous silica nanoparticles (MSN); Cu₂S; oxidized dextran (oDEX)

pH-responsive; PTT

MCD triggers tumor cell cuproptosis by inhibiting key proteins in TCA cycle. MCD effectively mitigates tumor growth and osteosarcoma-induced bone destruction in vivo under NIR-II light irradiation

[238]

CuET@PH NPs

Polydopamine; hydroxyethyl starch; copper-diethyldithiocarbamate (CuET)

Hyperbaric oxygen (HBO)

The combination of HBO and CuET@PH NPs potently suppresses energy metabolism of cancer stem cells, thereby achieving robust tumor inhibition of PDAC and significantly elongating tumor mice survival

[239]

PCD@CM

NIR-II ultrasmall polymer dots; Cu²⁺; DOX; 4T1 cell membrane

GSH-responsive; homotypic cancer cell membrane-mediated self-recognition and internalization; PTT

Cu released by PCD@CM induces the aggregation of lipoylated mitochondrial proteins accompanied by the loss of iron–sulfur proteins, leading to severe proteotoxic stress and eventually cuproptosis. NIR-II PTT and GSH depletion render tumor cells more sensitive to cuproptosis. The amplified cuproptosis significantly sensitized aPD-L1-mediated tumor immunotherapy

[240]

D-CuxOS@Fe-MOF

Cu²⁺; Fe³⁺; d-/l-penicillamine; NH2-BDC

pH-responsive

D-CuxOS@Fe-MOF induces augmented oxidative stress and potent ferroptosis, which synergizes with cuproptosis for enhanced cancer therapy

[241]

T-HCN@CuMS

Heterogeneous carbon nitride (HCN); Cu-loaded metallic molybdenum bisulfide nanosheets (CuMS); cRGDfk-PEG2k-DSPE

cRGDfk-PEG2k-DSPE-mediated specific recognition to αvβ3 integrins of tumor cells; PTT

T-HCN@CuMS presents a favorable photo-induced catalytic property to generate abundant ROS under NIR. It efficiently catalyzes the Fenton-like reaction and triggers cell cuproptosis, resulting in favorable therapeutic outcomes to inhibit tumor growth and metastasis

[242]

CQG NPs

Cu²⁺; polyvinylpyrrolidone (PVP); gallic acid; (3-aminopropyl) triethoxysilane (APTES); GOx

GSH-responsive

CQG NPs can induce cuproptosis by released Cu and depletion of GSH, and induce pyroptosis by disrupting the antioxidant defense mechanism of tumor cells, thereby enhancing the infiltration of immune cells into the tumor and activating robust systemic immunity

[243]