Table 1.
Different nano-adjuvants activate STING pathway.
| Drug | Materials | Effect and mechanism | Reference position |
|---|---|---|---|
| Metal-based nanoparticle adjuvants | |||
| CMPCDA | MnCl2,1 mg/mL CDNs solution,DOPE-H11 | Adding Mn2+to different concentrations of cGAMP can significantly enhance the type I IFN response of THP1 cells expressing hSTINGR232, hSTINGH232 and hSTINGHAQ. CMP can significantly enhance the activation of ST agonist,ST activation and IFN-β response of THP1 cells in vitro. | [40] |
| HBMn-FA NPs | 0.625 mol/L (NH₄)₂CO₃ solution (containing 8mg/mLHemin),13.3 mg/mL PLGA/DCM solution),1 mol/L MnCl₂ solution,10 mg/mL BSO solution,BSA solution,DSPE-PEG-FA,Milli-Q water | Specifically activating and amplifying cGAS-STING pathway in both tumor cells and antigen presenting cells; skillfully avoiding the delivery difficulty of STING agonists via the activation of STING by endogenous signaling; and.significantly enhancing the therapeutic efficacy of immune check point blockade (a PD-1)to activate systematic immunotherapy. | [41] |
| TriNV | MON (Mesoporous Organosilica Nanoparticle),10 mg/mL Polyethyleneimine (PEI) Solution, KMnO4, H2O, Oleic Acid (OA), 5 mg/mLPoly (allylamine hydrochloride) Solution (PAH), 5 mg/mL,Poly (acrylic acid) Solution (PAA):,Amino-terminated PEG (mPEG-5K-NH2), EDC (Likely 1-Ethyl-3-(3-Dimethylaminopropyl) Carbodiimide, a crosslinking agent), Indocyanine Green (ICG) | ISTVs improve the uptake of TAA by DC cells in the tumor microenvironment, enhance their acquired immunity, and finally, due to the release of Mn2+ in the tumor microenvironment from ISTVs and the synergistic effect with dsDNA released from the rupture of cancer cells caused by photothermal therapy, the activation of the cGAS-STING pathway is promoted, which further promotes the maturation of DC and the polarization of macrophages to M1, thus amplifying the T cell immune response. | [42] |
| CM@Mn | KMnO4,OA,4T1The tumor cell membrane (CM) | A large amount of reactive oxygen species (ROS) is produced in cells to promote cell death, which leads to a large amount of DNA release to activate STING pathway and stimulate the activation of immune cells | [43] |
| G5-pBA/OVA@Mn | G5-PAMAM dendrimer, OVA,3-(bromomethyl) benzoic acid (mBA) and 4-(bromomethyl) benzoic acid (pBA),MnCl2 solution | Because tumor antigen OVA is attached to G5-pBA, DC cells uptake tumor antigen and accelerate the release of Mn2 +, thus activating STING pathway to accelerate the maturation of immune cells such as CD+8 and release immune factors such as IFN-γ. | [44] |
| ZnS@BSA | Bovine serum albumin (BSA),Zn(CH3COO) 2,Na2S | Zn ∼ (2 +) and S ∼ (2-) are released in the acidic environment of tumor cells. Sulfur ion and H ∼ (2 +) in tumor cells lead to the accumulation of ROS and the release of mitochondrial DNA, which activates the STING pathway. Zn ∼ (2 +) enhances the activity of cGAS catalytic enzyme and enhances the STING signal | [45] |
| CFCP | methanol,ethanol, Acetone,1,3,5-Tris (4-aminophenyl)benzene (TAPB),Benzene-1,3,5-tricarbaldehyde (BTC),glacial acetic acid, FeCl3.6H2O, curcumin,H2PtCl6,NaBH4 | Under the mediation of CFCP and its standardization, the cell membrane of tumor cells is destroyed, accelerating cancer cell death in synergy with iron ions. This process releases dsDNA and activates the STING pathway, promoting dendritic cell (DC) maturation. Additionally, it amplifies immune stimulation through interferon induction, thereby inducing systemic immunity | [46] |
| IONP-C/O@LP | denoted as dip-PEG-mal, Fe3O4,thiol-modified CpG,thiol-modified OVAp | Through targeted delivery of OVAp and CpG to the immature DC cytoplasm and lysosomes, the activation rate of DC cells is enhanced and the accumulation of reactive oxygen species is induced, further activating the STING pathway. | [47] |
| Advantages and Disadvantages | Advantages: 1.Metal-based nano-adjuvants for tumor vaccines leverage the size advantage of nanomaterials, enabling them to concentrate more easily in lymph nodes, spleens, and other lymphatic organs. This improves their effectiveness in stimulating the immune response.2.Metal nano-adjuvants, while delivering antigens or drugs, can also activate immune pathways on their own. Metal ions such as Mn2+, Zn2+, and Ca2+ have the ability to trigger immune pathways, further enhancing the immunogenicity of the vaccine Disadvantages:1.During the delivery process, metal nano-adjuvants may be influenced by the internal environment, resulting in unstable drug release or inaccurate targeting to the desired site. This can compromise their therapeutic effectiveness.2.The immunological mechanisms underlying the actions of metal nano-adjuvants in tumor vaccines are not yet fully understood. This lack of clarity may hinder the prediction and optimization of their therapeutic outcomes. |
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| Nano adjuvant based on platinum/camptothecin -based chemotherapy drugs | |||
| PC7APolymeric Nanoparticles | ester coupling of 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid,2- (azepan-1-yl)ethanol,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1,3-dioxane heterocycle trifluoroacetic acid,ethyl-2,6-diisocyanatohexanoate,polyethylene glycol,1H and 13C NMR,Oxa-C16,1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-[polyethyleneglycol2000]ammonium (DSPE-PEG 2000) | PC7A is capable of binding to STING protein and activating STING pathway effectively. Moreover, cisplatin within it can induce DNA damage, releasing DNA to further activate STING pathway | [48] |
| CPT-SS-OA/CM | Oleic acid (OA),2,2-dithiodiethanol or hexanediol, dichloromethane (DCM),CPT,DMAP, Triphosgene,ethanol, Cremophor EL | CPT-SS-OA/CM can be easily internalized into cells and converted into active ester CPT, which activates the cGAS-STING pathway, promoting the maturation of DC cells and the tumor infiltration of CD8+ T cells. Additionally, it reduces the inherent toxicity of camptothecin. | [49] |
| CPT-S-S-LA | OH-S-S-OH(DTDE),triethylamine, tetrahydrofuran (THF),dichloromethane (DCM),NaHCO3,NaN3,N-Dimethylformamide (DMF),lactobionic acid,trifluoroacetic acid | This medication can target the accumulation of CPT at the site of liver cancer tumors, release CPT in tumor cells, induce apoptosis in tumor cells, release tumor DNA, activate a strong STING immune response, and have fewer toxic side effects from CPT. | [50] |
| CPT-Pt (Ⅳ) | Mercaptoacetic acid, trifluoroacetic acid, acetone, lithium aluminium hydride, triphosgene, succinic anhydride, 1,2,4,5-cyclohexa netetracarboxylic dianhydride, mPEG2k-DSPE, and 3-(4,5-dimethylth iazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) Hexadecyl iso cyanate, Cisplatin,Irinotecan hydrochloride trihydrate (CPT-11) | CPT-Pt (Ⅳ) can facilitate the maturation of BMDCs, leading to the accumulation of reactive oxygen species (ROS) in cancer cells, the disruption of mitochondria and the release of DNA, activation of the cGAS-STING pathway, and the subsequent release of type I interferon, promoting DC cell maturation. | [51] |
| SSC-1,SSC-2,and SSC-3 | K2CO3,allylbromide,N,N-Dimethylformamide (DMF)4-Dimethylaminopyridine,acetic anhydride,dry pyridine,dry CH2Cl2,C8H12N4(AIBN),2-mercaptoethoxy ethanol, compound 7,DMTrCl, Camptothecin | Promoting the accumulation of reactive oxygen species (ROS) triggers the disruption of mitochondrial membrane in cancer cells, leading to the release and assembly of mitochondrial DNA into double-stranded DNA (dsDNA). The binding of y with the CGAS protein inside cancer cells activates the STING pathway. | [52] |
| Advantages and disadvantages | Advantages: 1.Due to their nanoscale size, nano-adjuvants are capable of penetrating deep into tumor cells and precisely releasing chemotherapy drugs within the tumor microenvironment, thus effectively killing a large number of cancer cells.2.The extensive death of cancer cells caused by chemotherapy drugs releases a significant amount of dsDNA, which in turn strongly activates the cGAS-STING pathway, leading to a robust immune response. Disadvantages: 1.Chemotherapy drugs can cause damage to healthy cells as well, making the timing and location of their release a major concern. Ensuring the drugs are delivered specifically to tumor cells and released at optimal intervals is crucial.2.The loading capacity of nano-adjuvants for chemotherapy drugs determines their ability to trigger an immune response. Low drug loading represents a significant obstacle in the development of nano-adjuvants carrying chemotherapy drugs. |
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| DNA nano-adjuvant | |||
| DNA-based nanotubes | oligonucleotides, Atto488-dUTP,Cy3-dUTP,CoCl2,terminal transferase enzyme | CpG oligonucleotides with the DNA tubes promote the production of TNF-α, thereby activating the STING pathway. | [53] |
| Advantages and disadvantages | Advantages: 1. DNA nano-adjuvant tumor vaccines leverage the unique properties of nanomaterials to achieve efficient targeted delivery of drugs or antigens, ensuring their precise localization to tumor tissues while minimizing off-target distribution.2.By optimizing the antigen delivery system, DNA nano-adjuvants can enhance the immune response to vaccines, thereby improving their immunogenicity. Disadvantages: 1.The preparation process of DNA nano-adjuvants is relatively complex, requiring precise control over parameters such as nanoparticle size, shape, and surface properties to ensure efficient delivery and stable release in vivo.2.Due to the complexity of the preparation process and the specificity of the required materials, the cost of DNA nano-adjuvants tends to be relatively high. |
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| Other | |||
| PC7A NP | antigen, polymeric nanoparticle | It induces a strong cytotoxic T cell response and reduces the expression of systemic cytokines. Mechanistically, PC7A NP achieves effective cytoplasmic delivery of tumor antigens to APCs in draining lymph nodes, leading to increased surface presentation while activating the STING pathway, subsequently activating type I interferon-stimulated genes | [54] |
| STING-NPs | Butyl methacrylate (BMA), poly (ethylene glycol)4-cyano-4-(phenylcarbonothioylthio)pentanoate, Mn = 2000 Da and Mn = 10,000 Da (PEG-CPADB),4cyano-4-(phenylcarbonothioylthio)pentanoate (CPADB), N,N′-Dicyclohexylcarbodiimide (DCC),4-(Dimethylamino)pyridine (DMAP), DL-Dithiothreitol (DTT), 4,4′-azobis (4 Cyanovaleric acid) (V501), dichloromethane,1,4-dioxane,and poly (ethylene glycol) methyl ether (Mn = 5,000Da)2-(Diethylamino)ethyl methacrlate (DEAEMA) 2,2′-Azobis (4 methoxy-2,4-dimethylvaleronitrile) | Increased bioactivity of cGAMP enhances the STING signaling in the tumor microenvironment and sentinel lymph nodes, transforming the immunosuppressive tumor into an immunogenic tumor-killing microenvironment. This leads to enhanced therapeutic efficacy of cGAMP, suppressing tumor growth, improving long-term survival rates, amplifying response to immune checkpoint blockade, and inducing immune memory to protect against tumor re-challenge. | [55] |
| DMXAA | flavone-acetic,5,6-dimethylxanthenone-4-acetic,Flavone-8-Acetic Acid | Activate the immune system to increase the quantities of white blood cells, interleukin-6, tumor necrosis factor, and chemokines, inducing cellular apoptosis and activating the STING pathway. | [56] |
| MOF-Cp G-DMXAA | Fumaric aicd,CpG ODNs,DMXAA,MOF-801,Zr6 clusters,DNA (50 μm,uniform size and zeta potential at around +45 mV) | Can polarize TAMs in the cell to promote the maturation of DC cells, including DMXAA, which can activate the STING pathway. Metal-Organic Framework (MOF-801) can be recognized by TLR4 to activate the STING-NF-κB pathway, thereby promoting the maturation of dendritic cells. | [57] |
| MONCPT | 2O(S)-camptothecin,10-hydroxy-20(S)-camptothecin,10-methoxy-20-(S)-camptothecin,DMSO solution | Regulate the expression of matrix metalloproteinase-9, control the cell cycle, induce extensive cell death, release DNA to activate the cGAS-STING pathway, and promote DC cell maturation. | [58] |
CMPCDA:CMP,CDN-Mn2+particle,CDN,cyclicdinucleotide; CDA,c-di- AMP,AMP,a denosine monophosphate; CM@Mn:CM,tumor cell membrane; G5-PAMAM,Poly(a midoamine) dendrimer; ZnS@BSA: BSA,bovine serum albumin; CFCP: iron-base d covalent organic framed nanoadjuvant doped with curcumin and platinum; IO NP-C/O@LP: IONP, iron oxide nanoparticles; L,encapsulated by lipid film; P,bearin g a DC-targeting cyclic peptide P30; PC7A,encapsulation of chemotherapeutic pl atinum complexes with a polymer with a cyclic seven-membered ring; CPT-SS- OA: CPT,camptothecin; SS,disulfide bond; OA,oleic acid; CPT-S-S-LA: LA,lactose; SSC,Aptamer−drug conjugates; PC7A NP, a minimalist nanovaccine by a simplephysical mixture of an antigen with a synthetic polymeric nanoparticle; STING- NPs: STING, agonists o stimulator of interferon genes; DMXAA, Vadimezan; MOF-CpG-DMXAA:MOF,metal-organic framework; CpG,cytosine-phosphate-guanine; MONCPT,a topoisomerase I inhibitor.