Table 3.
The nanomaterials for delivery of STING agonists
| Nanomaterials | Encapsulated STING agonists | Encapsulated anti-tumor agents | Key design features | Targeting components of STING pathways | in vivo model | Ref |
|---|---|---|---|---|---|---|
| Liposome | cGAMP | N/A | Mannose-coated NPs for DCs’ reorganization and uptake | Upregulation of IFN-β and IL-12 | V600E BRAF-mutated and B16F10 melanoma model | [53] |
| cGAMP | N/A | Phosphatidylserine-coated surface for APCs’ reorganization and uptake | Upregulation of IFN-β, TNF-α, IL-6, p-TBK1 and p-IRF3 | 4T1 breast cancer and B16-OVA melanoma model | [54] | |
| cGAMP | N/A | A photothermal segment (FeS2) for generating hydroxyl radic; bromelain-modified surface for ECM degradation | Upregulation of TNF-α and IL-6 | 4T1 breast cancer model | [56] | |
| CDG | MPLA | The hydrophilic CDG into the NP core and hydrophobic MPLA into the lipid bilayer | Upregulation of IFN-β and TNF-α | B16F10 melanoma, 4T1 and D2.A1 breast cancer model | [138] | |
| CDG | MPLA | The hydrophilic CDG into the NP core and hydrophobic MPLA into the lipid bilayer | Upregulation of IFN-β | Panc02 pancreatic cancer model | [137] | |
| diABZI | αPD-L1 and αCD47 | A lipid NP with dual linkages of αCD47 and αPD-L1 | Upregulation of TNF-α, CXCL9 and CXCL10 | CT-2 A and PVPF8 glioma model | [129] | |
| Polymersomes | cGAMP | N/A | pH-sensitive segments (DEAEMA) with hydrophobic BMA for endosomal escapes | Upregulation of IFN-β, CXCL9 and CXCL10 | B16F10 melanoma model | [59, 62] |
| cGAMP | N/A | pH-sensitive segments (DEAEMA) with hydrophobic BMA for endosomal escapes | Upregulation of IFN-β, TNF-α, IL-12, CXCL10 and p-IRF3 | B16F10 melanoma model | [61] | |
| cGAMP | N/A | pH-sensitive segments (DEAEMA) with hydrophobic BMA for endosomal escapes | Upregulation of IFN-β, CXCL10, TNF, IL-12, p-IRF3 | Neuro-2a and 9464D neuroblastoma model | [60] | |
| cGAMP | Tumor antigen (OVA) | pH-sensitive segments (DEAEMA) with hydrophobic BMA for endosomal escapes | Upregulation of IFN-α, IFN-β, TNF-α and IL-6 | B16F10 melanoma and MC38 colorectal cancer model | [133] | |
| Micelles | cGAMP | N/A | PC7A NP as a polyvalent STING agonist for amplifying activation of STING pathway | Upregulation of IFN-β and CXCL10 | MC38 colorectal cancer model | [68] |
| cGAMP | Tumor antigen (OVA) | A cationic PDMA for electrostatic complexation with negatively charged cGAMP; a pH-responsive segment (PDPA) for NPs’ cellular disassembly and endosomal escapes | Upregulation of IFN-β, TNF-α, CXCL9, CXCL10 and IL-12 | EG7 lymphoblastoma, MC38 colorectal and TC-1 cervical cancer model | [69] | |
| Other Polymeric NPs | DMXAA | Tumor antigen (OVA) | Co-assembly of PEG-b-PDPA diblock copolymer with OEI-C14 for facilizing endosome escapes; surface modification with mannose for APCs’ reorganization | Upregulation of IFN-β, TNF-α, IL-6, CXCL10, Isg-15, p-IRF3 and p-TBK1 | B16-OVA melanoma and 4T1 breast cancer model | [132] |
| DMXAA | SN38 | SN38-grafted block as a chemotherapeutic prodrug; amine-containing DEAEMA group providing a positive charge for effective encapsulation and cellular internalization | Upregulation of IFN-β, TNF-α, CXCL9, CXCL10 and IRF7 | B16F10 melanoma and 4T1 breast cancer model | [63] | |
| CDNs | N/A | Cationic PBAEs as carriers for binding CDNs, specific cellular uptake and effective endosomal escapes | Upregulation of IRF3 | B16F1 melanoma model | [86] | |
| diABZI | αPD-L1 and Gemcitabine | αPD-L1-coated surface for enhancing cellular uptake and antitumor efficacy; Gemcitabine-PLA segment as a chemotherapeutic prodrug | Upregulation of IRF7, IL-6, CXCL9, CXCL10 and IFN‐β | Panc02 pancreatic cancer, B16F10 melanoma and 4T1 breast cancer model | [125] | |
| cGAMP | siSIRPα | cationic lipid DOTAP and PEG-b-PLGA forming NPs that enhances encapsulation efficiency and cellular uptake | Upregulation of IFN-α and IFN-β | B16F10 melanoma model | [87] | |
| 3′3 cGAMP | CpG ODNs, 5′ppp-dsRNA, and tumor antigen (TRP2) | carboxylic acid-terminated PLGA for preventing aggregation and embolisms upon intravenous injection | Upregulation of TNF-α and IL-12 | B16F10 melanoma model | [88] | |
| CDG | αCD47 | MPC as a zwitterionic polymer for superior BBB penetration; a FAP-α-responsive crosslinker targeted by the FAP-α enzyme in TME for effective release of CDG | Upregulation of IFN-β and TNF-α | GL261 glioma model | [127] | |
| cGAMP | Tumor antigen (OVA) | Self-degradable framework PBAEs for endosomal escape | Upregulation of IFN-β, TNF-α, CXCL9 and CXCL10 | B16F10 melanoma model | [89] | |
| Mn2+-based NPs | CDA | N/A | Mn2+ as a STING agonist that self-assembles with CDNs and amplifies STING activation | Upregulation of IFN-β, TNF-α, CXCL-9 and CXCL10 | B16F10 melanoma and CT26 colorectal cancer model | [71] |
| INOP-based NPs | MSA-2 | Tumor antigen (OVA) | Acid INOPs for augmenting STING activation and endosomal escapes | Upregulation of IFN-β, TNF-α, IL-6 and CXCL10 | B16-OVA melanoma and MC38 colorectal cancer model | [72] |
| Zinc-based NPs | CDA | N/A | A non-toxic zinc phosphate hydrophilic core with surrounding lipid bilayer | upregulation of IFN-β, TNF-α and IL-6 | B16F10 melanoma. MC38 colorectal cancer and GL261 glioma model | [73] |
| MOFs | SR-717 | N/A | A photosensitizer (TCPP) for controlling oxidation-responsive SR-717 release | Upregulation of IFN-β and IL-6 | 4T1 breast cancer model | [78] |
| DMXAA | CpG ODNs | MOF-801 as a STING agonist that self-assembles with DMXAA and CpG ODNs | Upregulation of IL-6, TNF-α, and cGAS-STING-NF-κB signaling | Hepa1-6 hepatoma carcinoma model | [141] | |
| Mesoporous silica | CDG | N/A | Amine-modified surface electrostatically interacts with the anionic phospholipid membrane and ECM for enhancive local adherence | Upregulation of TNF-α | B16F10 melanoma model | [81] |
| CDG | N/A | PEGylated modification and quaternary ammonium-modified surface for stable blood circulation, enhancive tumor accumulation, and cellular uptake | Upregulation of IL-1β, IFN-β, IL-6 and p-STING | 4T1 breast cancer model | [82] | |
| CDG | N/A | Amine functionalization facilitating high CDG loading and effective release of CDG upon cellular internalization. | Upregulation of IFN-β | GL261 glioma model | [83] | |
| CDA | N/A | A larger pore size (5–10 nm) and a thinner Si-O-Si matrix for rapid release of CDA | Upregulation of IFN-β, CXCL10, CCL2, and CCL5 | B16F10 melanoma model | [84] | |
| Sono-driven NPs | MSA-2 | N/A | A semiconducting polymer as a sonosensitizer that links with MSA-2 through a singlet oxygen cleavable linker (diphenoxyethene) | Upregulation of IFN-β, p-TBK1 and p-IRF3 | SCC-7 head and neck squamous cell carcinoma model | [91] |
|
Lipid nanodisc (LND) |
CDNs | N/A | A flexible high-aspect-ratio morphology for improving penetration capacity; the conjugation of CDN prodrug and LND could be cleaved by cathepsin after cellular internalization | Upregulation of IFN-β, TNF-α and IL-6 | MC38 colorectal cancer, TC-1 cervical cancer and 4T1 breast cancer model | [93] |
|
Supramolecular NP |
CDG | N/A | A hydrophobic nucleotide lipid (3’,5’-diOA-dC) assembling with CDG through various supramolecular forces | Upregulation of IFN-β, TNF-α, CXCL9, CXCL10, STING and p-IRF3 | B16F10 melanoma model | [95] |
| Extracellular vehicles (EVs) | CDNs | N/A | EVs as a delivery vehicle with favorable biocompatibility | upregulation of IFN-β, CXCL-9 and CXCL10 | B16F10 melanoma and CT26 colorectal cancer model | [97] |
Abbreviations: p-TBK1: phosphorylated TBK1; p-IRF3: phosphorylated IRF3; p-STING: phosphorylated STING; OVA: ovalbumin; ECM: extracellular matrix; αCD47: CD47 antibody: αPD-L1: PD-L1 antibody; DEAEMA: 2-diethylaminoethyl methacrylate; BMA: butyl methacrylate; PBAEs: Poly (beta-amino esters); PLA: poly(lactic acid); MPC: 2-methacryloyloxyethyl phosphorylcholine; FAP-α: fibroblast activation protein α; PDMA: poly((2-dimethylaminoethyl) methacrylate; PDPA: poly(2-(diisopropylamino)ethyl methacrylate); INOPs: Acid-ionizable iron NPs; MOFs: metal–organic framework; TCPP: meso-tetra(carboxyphenyl)porphyrin; PLGA: poly(lactic-co-glycolic acid); DOTAP: 1,2-dioleoyl-3-trimethylammonium-propane; PEG: polyethylene glycol; Isg-15: Interferon stimulated gene 15