Table 1.
Tissue-targeted LNP. (DLS, dynamic light scattering; i.m., intramuscular; i.v., intravenous; s.c., subcutaneous; i.d., intradermal; i.p., intraperitoneal; r.o., retroorbital; PDI, polydispersity index; ZP, zeta potential).
| LNP Targeting Components or Properties | Physicochemical Properties (DLS Size, PDI and Zeta Potential) |
Route of Administration | Payload and Indication | Model | Tissue/Cell Type Specificity | Ref. |
|---|---|---|---|---|---|---|
| 50 mol% 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) |
113 nm 0.22 PDI −0.52 mV |
i.v. | human Erythropoietin, mouse Interleukin-10, mouse Klotho, Luciferase and Cre mRNA, and Cas9 mRNA/sgTom1 * | 18–20 g male C57BL/6 mice; (age and sex not specified) B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J mice (also known as Ai9 or Ai9(RCL-tdT) mice |
hepatocyte uptake | [17] |
| 30 molar% 1,2-dioleoyl-sn-glycero-3-phosphate (18PA) |
142 nm 0.13 PDI −2.11 mV |
i.v. | human Erythropoietin, mouse Interleukin-10, mouse Klotho, Luciferase and Cre mRNA, and Cas9 mRNA/sgPTEN and Cas9 mRNA/sgTom1 * | 18–20 g male C57BL/6 mice; (age and sex not specified) B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J mice (also known as Ai9 or Ai9(RCL-tdT) mice |
hepatocyte uptake | [17] |
| 20 molar% 1,2-dioleoyl-3-dimethylammonium-propane (DODAP) |
12 nm 0.18 PDI (ZP not specified) |
i.v. | human Erythropoietin, mouse Interleukin-10, mouse Klotho, Luciferase and Cre mRNA, and Cas9 mRNA/sgPCSK9 and Cas9 mRNA/sgTom1 * | 18–20 g male C57BL/6 mice; (age and sex not specified) B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J mice (also known as Ai9 or Ai9(RCL-tdT) mice |
hepatocyte uptake | [17] |
| 50:10:38.5:1.5% mole ratios DLin-KC2 DMA:DSPC:Cholesterol: DMG-PEG2000, with N:P molar ratio = 2, imparting negative charge |
75 nm (PDI not specified) −10 mV |
i.m. | Luciferase mRNA * | 8-week-old female Balb/c mice |
greater hepatic distribution following i.m. administration | [4] |
| 50:23.5:6.5:20% mole ratios 7C1 **:C14PEG2K:18:1 Lyso PC 60:10:25:5% mole ratios 7C1 **:C14PEG2K:DOPE |
20–200 nm (PDI not specified) (ZP not specified) |
i.v. | ICAM-2 siRNA, Cre mRNA, CRISPR-Cas9 mRNA and ICAM-2 sgRNA * | 5–12-week-old (sex not specified) LSL-Tomato, C57BL/6J, and constitutive SpCas9 mice |
lung, spleen, liver and kidney endothelial cell uptake | [37] |
| Endogenous absorption of apoE to neutral LNP | 64.5 nm (PDI not specified) (ZP not specified) |
i.v. | Factor VII siRNA * | 6–8-week-old female C57Bl/6, ApoE−/− and LDLR−/− mice |
hepatocyte uptake | [29] |
| N-acetylgalactosamine (GalNAc) ligand | 69.4 nm (PDI not specified) (ZP not specified) |
i.v. | Factor VII siRNA * | 6–8-week-old female C57Bl/6 and ASGR2−/− mice |
hepatocyte uptake | [29] |
| Plasmalemma vesicle-associated protein (PV1) | 70 nm, 0.104 PDI and 160 nm, 0.150–0.240 PDI (ZP not specified) |
i.v. | Luciferase mRNA, Cy5-mRNA * | 5-week-old female Balb-c mice |
lung uptake | [7] |
| Anti-Ly6c mAbs | 70 nm (PDI not specified) (ZP not specified) |
i.v. | Luciferase or IL-10 mRNA; treatment of inflammatory bowel disease |
Colitis was induced in: 12-week-old female C57BL/6 mice using dextran sodium sulfate |
leukocyte uptake | [38] |
| 15–20 mol% C18PEG2000:80 mol% 7C1 **:0.1–10 mol% cholesterol | 45–50 nm <0.2 PDI (ZP not specified) |
i.v. | ICAM-2 siRNA, ICAM-2 targeting sgRNA * | 5–12-week-old (sex not specified) C57BL6/j and constitutive SpCas9 mice |
bone marrow endothelial cell | [39] |
| Anti-CD4 antibody | 129 nm 0.12 PDI −10 mV |
i.v. | Cy5-labeled siRNA and CD45 siRNA * | 6–8-week-old (sex not specified) C57BL6/j mice |
T cells | [9] |
| Anti-CD4 antibody | 88 nm 0.1 PDI (ZP not specified) |
i.v. | Cre recombinase-encoding mRNA * | (age not specified) (sex not specified) Ai6 (RCL-ZsGreen) mice on C57BL/6J |
Splenic and lymph node T cells | [10] |
| Adamantane-constrained lipid | 20–200 nm 0.20–0.23 PID (ZP not specified) |
i.v. | GFP siRNA * | 5–8-week-old female C57BL/6-Tg(UBC-GFP)30Scha/J, ‘GFP mice’ |
splenic T cells | [40] |
| Anti-CD29 antibody | 66–75 nm 0.10–0.16 PDI (ZP not specified) |
i.v. | PLK1 siRNA; treatment of disseminated bone marrow mantle cell lymphoma xenograft |
8-week-old female C.B-17/IcrHsd-Prkdc scid mice |
mantle cell lymphoma | [8] |
| Cholesterol oleate | 22–115 nm (PDI not specified) (ZP not specified) |
i.v. | ICAM-2 siRNA, GFP-targeted sgRNA * | 5–8-week-old female C57BL/6J and C57BL/6-Tg(UBC-GFP)30Scha/J, ‘GFP mice’ |
hepatic endothelial cells | [41] |
| ~30 nm, negatively charged LNP | 34 nm 0.242 PDI −12 mV |
s.c. | DiD-labeled LNP (no nucleic acid) * | 7–9-week-old female C57BL/6J mice |
CD8+ dendritic cells/lymph node | [14] |
| 35:5:55:5% mole ratios 7C1 **:Cholesterol:C14PEG2000:DOTAP |
40 nm (PDI not specified) (ZP not specified) |
nebulization | Therapeutic membrane-anchored FI6 antibody mRNA, H1N1 influenza model | 6–8-week-old female BALBc mice |
lung | [42] |
| ~150 nm size, ~0.5% PEG density | 150 nm <0.1 PD (ZP not specified) |
intravitreal and subretinal injection | Cre, mCherry, luciferase mRNA * | 1–6 months old male and female Albino BALB/c, Ai9, apoE−/−, Mertk−/− and C57BL6 mice |
optic nerve, trabecular meshwork, retinal pigment epithelium, Muller glia | [43] |
| Ionizable lipids with low pKa and unsaturated hydrocarbon chains | 83–229 nm 0.09–0.28 PDI (ZP not specified) |
subretinal injection | Luciferase, EGFP, mCherry mRNA * | 1–4 months old male and female Albino BALB/c mice |
retinal pigment epithelium | [44] |
| Oxidized cholesterol | ~80 nm 0.16 PDI (ZP not specified) |
i.v. | Cre mRNA * | 5–8-week-old (sex not specified) Ai14 Lox-Stop-Lox-tdTomato and C57BL/6J mice |
hepatic endothelial and Kupffer cells | [30] |
| Anti PECAM-1 antibody | 103 nm 0.195 PDI −4.1 mV |
i.v. | Luciferase mRNA * | (age not specified) (sex not specified) C57BL/6 mice |
lung vascular endothelial and immune cells | [11] |
| Adamantyl-constrained lipid | 100 nm (PDI not specified) (ZP not specified) |
i.v. | Cre mRNA * | (age not specified) (sex not specified) Ai14 Lox-Stop-Lox-tdTomato mice |
hepatic Kupffer cells | [31] |
| ApoE opsonization | 55 nm 0.058 PDI (ZP not specified) |
intracranial | PTEN, luciferase and GRIN1 siRNA * | 26–30-day-old (sex not specified) Sprague Dawley rats |
CNS neurons | [45] |
| CH6 osteoblast-specific aptamer | 84 nm (PDI not specified) (ZP not specified) |
i.v. |
osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA; treatment of impaired bone formation (e.g., osteoporosis) |
6-month-old female Sprague Dawley rats |
osteoblasts | [46] |
| Mannose-cholesterol | ~140 nm >0.2 PDI (ZP not specified) |
i.d. | Influenze hemagglutanin saRNA; H1N1 influenza vaccine |
6−8-week-old female BALB/c mice |
dendritic cells | [12] |
| Mannose-PEG-DSPE | ~100 nm (PDI not specified) (ZP not specified) |
i.v. | Cre mRNA and FVIII siRNA * | 7–10-week-old female C57BL/6 mice; 8-week-old (sex not specified) Lox-Stop-Lox-tdTomato |
hepatic endothelial cells | [13] |
| EGFR-antibody | 79 nm 0.085 PDI 7.7 mV |
i.p. | Cas9 mRNA, (polo-like kinase) PLK1 sgRNA; disseminated ovarian cancer |
8-week-old female Hsd: Athymic Nude-Foxn1nu mice with OV8 ovarian cancer peritoneal xenograft |
disseminated ovarian cancer | [47] |
| DEC205-antibody | 90–130 nm 0.12–0.20 PDI (ZP not specified) |
r.o. | CD40, CD80 and CD86 siRNA | 6–12-week-old (sex not specified) C57BL/6 mice, inhibition of mixed lymphocyte response to LPS |
CD8 alpha+ dendritic cells | [48] |
| CD4-antibody | 88 nm 0.1 PDI (ZP not specified) |
i.v. | Luciferase and Cre mRNA * |
(age not specified) male and female C57BL/6 and Ai6 (RCL-ZsGreen) mice on C57BL/6J background |
CD4+ T cells | [10] |
| CD5-antibody | 80 nm 0.02–0.06 PDI (ZP not specified) |
i.v. | CAR mRNA against fibroblast activation protein and Cre mRNA, cardiac fibrosis prevention |
(age not specified) (sex not specified) C57BL/6NAi6 Cre-reporter mice (Rosa26CAG-LSL-ZsGreen) |
CD5+ T cells | [49] |
* Experimental system, no therapeutic indication evaluated. ** 7C1 is a novel ionizable lipid; refer to publication for structure.