Table 2.
Summary of advanced nanoformulations for targeted delivery of mRNA to specific subsets of immune cells.
| Targeted immune cells | Nanoformulations | mRNA encoded molecules | Size (nm) | Surface charge (mV) | Tumor models | Mechanisms | Therapeutic outcome | Administration routes | Ref |
|---|---|---|---|---|---|---|---|---|---|
| Nano-mRNA targeting DCs | |||||||||
| Ex vivo DCs | Cationic liposomes/iron oxide NPs | OVA | 207.9 ± 67.2 | 44.1 ± 4.5 | B16F10-OVA murine melanoma | Activating DCs and promoting antigen expression | Suppressing tumor growth | i.d. | [137] |
| Ex vivo DCs | Lipoplex/vitamin E scaffold/peptide | OVA | / | / | E.G7-OVA murine lymphoma | As above | Suppressing tumor growth | s.c. | [138] |
| Ex vivo DCs | Chitosan NPs | CD40+ICOSL | 35 | / | 4T1 murine breast cancer | Activating DCs, promoting T proliferation and accelerating cytokine secretion | Suppressing tumor growth | i.t. | [139] |
| Splenic conventional DCs, pDCs and macrophage | Lipoplex | OVA; gp70; TRP-1; CT26-M90; HPV E6/E7 | 200–400 | / | B16-OVA and B16F10-Luc murine melanoma, CT26 and CT26-Luc murine colon carcinoma and TC-1-Luc murine cervical cancer | Activating DC and priming CD4+ and CD8+ T cells via TLR7-IFNα signaling pathway | Regression of tumor/suppressing tumor growth | i.v. | [21] |
| As above | Lipoplex | CLDN6 | / | / | xenograft OV-90 human ovarian cancer | Driving proliferation of adoptive CLDN6-CAR-T cells | Regression of tumor/suppressing tumor growth | i.v. | [34] |
| DCs | C1 LNP | OVA | 150 | 16.37 ± 0.404 | B16-OVA murine melanoma and MC38-OVA murine colon carcinoma | Activating DCs via TLR4 pathway | Suppressing tumor growth | s.c. | [25] |
| dLN-DCs, NK cells, macrophages and B cells | OMV/clyA-L7Ae/clyA-LLO | OVA; | 28.1 | / | B16-OVA murine melanoma and MC38 murine colon carcinoma | Activating DC via multiple TLR pathways | Regression of tumor/suppressing tumor growth | s.c. | [24] |
| ADPGK | |||||||||
| dLN-DCs | Hydrogel | OVA | 220 | −0.52 | B16-OVA murine melanoma | Sustained release of delivered R848 and mRNA for enhanced DC activation via TLR7/8 pathway | Suppressing tumor growth | s.c. | [145] |
| (PEI + GO) | |||||||||
| DCs | PLGA/lipid NPs | OVA | 400 | 20 | B16-OVA murine melanoma | Delivery of gardiquimod for DC activation via TLR7 pathway | Suppressing tumor growth | i.v. | [119] |
| dLN-DCs, neutrophils, macrophages, and B cells | LNPs | Gp100; TRP2; OVA; | 200 | −14.1–2.0 | B16F10 and B16-OVA murine melanoma | LNPs delivered modified mRNA and LPS for enhanced DC activation via TLR4 pathway | Suppressing tumor growth | s.c. | [146] |
| DCs | PEG/lipid/polymer NPs | OVA | 137 ± 2.8 | 11.2 ± 2.1 | E.G7-OVA murine lymphoma and RM1-OVA murine prostate cancer | Delivery of C16-R848 for enhanced DC activation via TLR7/8 pathway | Suppressing tumor growth | s.c. | [147] |
| dLN-macrophages, DCs, | Heterocyclic LNPs | OVA; | 100 | / | B16F10-OVA murine melanoma and TC1 murine cervical cancer | Activating DCs via heterocyclic amine group-mediated STING pathway | Suppressing tumor growth | s.c. | [22] |
| and monocytes | E7 | ||||||||
| DCs | LNPs | E6/7; STINGV155M | 80–100 | / | TC-1 murine cervical cancer | Activating DCs via hypersensitive STINGV155M pathway | Suppressing tumor growth | i.m. | [155] |
| DCs | Manna/PEI nanocapsules | OVA | 220 | 32 ± 0.5 | B16F10-OVA murine melanoma | Activating DCs via dectin-2/TLR-4 | Suppressing tumor growth | s.c. | [158] |
| Splenic DCs and macrophages | Trimannose/lipid/polymer hybrid NPs | OVA; | 230 | 45 | TC-1 murine cervical cancer and B16-OVA murine melanoma | Priming anti-tumor T cells via nanoparticle mediated-type I-IFN pathway | Regression of tumor/suppressing tumor growth | i.v. | [132] |
| E7; | |||||||||
| CD40L + CD70+ cATLR4 | |||||||||
| dLN-DCs | Mannose/lipid-calcium/phosphate NPs | MUC1 | 58 | 38 | 4T1 murine breast cancer | Activating DCs via mannose receptor pathway | Suppressing tumor growth | s.c. | [124] |
| Splenic DCs | α-GC/liposomes | OVA | 190 | 47 | B16-OVA murine melanoma and E.G7-OVA murine lymphoma models | Activating DCs, iNKT and NK cell | Suppressing tumor growth | i.v | [159] |
| Systematic PD-L1+ APCs | LNPs | Whole tumor antigens; | 70–200 | 40–50 | B16F10 and B16-OVA murine melanoma; glioma | Activating PD-L1+DC | Suppressing tumor growth | i.v. | [160] |
| OVA | |||||||||
| DCs | Mesoporous silica NPs | OVA; | 115 | / | E.G7-OVA murine lymphoma | Promoting mRNA translation by loaded PKR inhibitor C16 | Regression of tumor/suppressing tumor growth | s.c. | [89] |
| GM-CSF; | |||||||||
| Lymphoid organ resident DCs | Lipoplex | PME1 | 340 | / | CT26 murine colon carcinoma | Local radiotherapy induced CD8+ T cells combined with nano-mRNA induced CD4+ T immunity for enhanced therapeutic effect | Regression of tumor/suppressing tumor growth | i.v. | [161] |
| DCs | Lipoplex | E7 | 200–250 | −20–30 | TC-1 murine cervical cancer | Activating DCs and inducing antigen-specific effector and memory CD8+ T cells | Regression of tumor/suppressing tumor growth | i.v. | [164] |
| DCs | Lipoplex | E7 | 200–250 | −20–30 | TC-1 murine cervical cancer | Local radiotherapy promoted nano-mRNA vaccine efficacy | Regression of tumor/Suppressing tumor growth | i.v. | [162] |
| DCs | Protamine | OVA | / | / | E.G7-OVA murine lymphoma | As above | Suppressing tumor growth | s.c. | [163] |
| Nano-mRNA targeting cytotoxic T cells and NK cells | |||||||||
| T cells | Anti-CD3/CD28 mAbs/PbAE/PGA(polyglycolic acido) polymer NPs | Foxo1 | 109.6±/26.6 | 1.1 ± 5.3 | Raji murine lymphoma | Reprogramming CAR-T cells to a memory phenotype with competent functions | Suppressing tumor growth | i.v. | [33] |
| T cells | Anti-CD8 mAbs/PbAE/PGA polymer NPs | CARs; TCRs | 106.9 ± 7.2 | / | Eμ-ALL01 leukemia, | In vivo reprograming of circulating T cells with CARs or TCRs | Suppressing tumor growth | i.v. | [32] |
| Raji lymphoma, LNCaP C42 prostate cancer and HepG2 hepatitis B-induced hepatocellular carcinoma models | |||||||||
| T cells | Phospholipid NPs | OX40; | 120–230 | 8–36 | B16F10 murine melanoma, A20 B cell lymphoma | Promoting T cell activation and therapeutic response to anti-OX40mAbs | Regression of tumor/Suppressing tumor growth | i.t./i.v. | [98] |
| CD137 | |||||||||
| T cells, macrophages, monocytes, granulocytes, DCs, tumor cells | LNPs | IL-23, IL-36γ, OX40L | / | / | H22 murine hepatocellular carcinoma, MC38 murine colon carcinoma, and B16F10-AP3 murine melanoma | Promoting the infiltration of multiple immune cells into tumor sites via cytokine- and OX-40L-mediated pathways | Regression of tumor/Suppressing tumor growth | i.t./s.c./i.d. | [173] |
| NK cells | LNPs | Anti-HER2 mAbs | / | / | mouse xenograft MDA-MB-231-HER2 human breast cancer | Enhancing NK-mediated ADCC | Suppressing tumor growth | i.v. | [30] |
| T cells | LNPs | Rituximab antibody | / | / | mouse xenograft human Raji lymphoma | CDC and ADCC | Regression of tumor/Suppressing tumor growth | i.v. | [175] |
| T cells | LNPs | Anti-PD-1 mAbs | / | / | MC38 murine colon carcinoma | Activating T cells by in vivo expression of therapeutic anti-PD-1 mAbs | Suppressing tumor growth | i.v. | [29] |
| T cells | Lipid/polymer NPs | CD3× CLDN6 bispecific antibodies | / | / | mouse xenograft OV-90, ES-2, ES-2/hCLDN6 human ovarian cancer | Bispecific T cell-engager mediated cytotoxic T cells to tumor cells | Regression of tumor | i.v. | [28] |
| Nano-mRNA targeting multiple immune cells in TME | |||||||||
| T cells, NK cells, macrophages | LNPs | IL-12a + IL12b | / | / | MC38-S and MC38-R murine colon carcinoma, B16F10-AP3 melanoma and A20 B cell lymphoma. | Driving Th1 immunity and activating DCs, T cells and NK cells | Regression of tumor/Suppressing tumor growth | i.t. | [133] |
| PDX model: ME 12057, ME 12058, HN 5111, HM5116 | |||||||||
| T cells, DCs, NK cells | LNPs | IL-12, IL-27, GM-CSF | 150–200 | / | B16F10 murine melanoma | Inducing robust infiltration of NK and CD8 T cells in tumor | Suppressing tumor growth | i.t. | [26] |
| T cells, NK cells, macrophages | LNPs | IL-12 | / | / | MYC-driven murine hepatocellular carcinoma | Promoting tumor infiltrating activated Th cells and production of IFN-γ | Suppressing tumor growth | i.v. | [184] |
| NK cells, T cells, | liposome-protamine complex | IL-15 | 221.33 ± 2.52 | 48.03 ± 1.429 | C26 murine colon cancer | Enhancing proliferation of NK, B, and T cells in tumor | Suppressing tumor growth | i.p./i.t/i.v. | [120] |
| TAMs, monocytes, DCs, neutrophils | Di-mannose/PbAE/PGA polymer NPs | IRF5 and IKKβ | 99.8 ±/24.5 | 3.40 ± /2.15 | ID8 murine ovarian cancer, B16F10 melanoma, and glioblastoma | Driving the polarization from M2-like macrophages to M1-like macrophages in tumor | Suppressing tumor growth | i.p./i.v. | [31] |
| T cells, DCs, NK cells | LNPs | CCL5 | / | / | B16F10 murine melanoma | CCL5 chemokine mediated recruitment of multiple | Suppressing tumor growth | i.t. | [27] |
| Leukocytes in tumor | |||||||||
| Tumor cells, T cells, DCs, macrophages | Charge-altering releasable transporters (CART) | CD70, OX40L, CD80, CD86, IL-12, IFN-γ | / | / | A20 murine B cell lymphoma and CT26 murine colon carcinoma | Cytokine mediated robust local T-cell activation and systematic immune response | Regression of tumor/Suppressing tumor growth | i.t. | [185] |
| Indirect targeting immune cells by nano-mRNA mediated immunogenetic cancer cell death | |||||||||
| Tumor cells | Lipid/mPEG-PLGA/G0-C14 hybrid NPs | PTEN | 111.8 ± 15.3 | / | Pten-mutated B16F10 murine melanoma and Pten-null/Pten-Cap8 murine prostate cancer | Inducing autophagy of cancer cells and release of immunogenic DAMPs | Suppressing tumor growth | i.v. | [179] |
| Tumor cells | Lipid/PLGA/G0-14/DSPE-PEG/CTCE NPs | p53 | 110 | negative | p53-null RIL-175 murine hepatocellular carcinoma | Promoting anti-tumor immune cells and decreasing pro-tumor immune cells | Suppressing tumor growth | i.v. | [35] |
| Tumor cells | liposome-protamine lipoplex | survivin-T34A | 186.1 ± 3.1 | / | C26 murine colon cancer | Inducing caspase-dependent cell apoptosis, and modulation of tumor microenvironment | Suppressing tumor growth | i.p./i.t./i.v. | [187] |
Note: i.v.: intravenous injection; i.m.: intramuscular injection; s.c.: subcutaneous injection; i.d.: intradermal injection; DSPE: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine.