Table 2 Targeting ligands used for directing therapies for different cell types in the brain

Transferrin

Transferrin antibody (OX26, 8D3, R17217)

Endothelial cells of the BBB

Transferrin receptor

Low tissue specificity; enriched in endothelial cells, bone marrow cells, and monocytes. In the brain is mostly expressed in microvasculature, neurons, and oligodendrocytes.

PLGA

Liposomes

[30, 80,81,82,83,84] + HPA*

ApoE

Angiopep-2

Endothelial cells of the BBB

Low Density Lipoprotein Receptor (LDLR)

Tissue enriched: adrenal gland; in the brain is mostly expressed in excitatory neurons and endothelial cells of the BBB.

PBCA

Human serum albumin-based NPs

[85,86,87,88,89] + HPA*

Insulin

Insulin antibody (29B4)

Endothelial cells of the BBB

Insulin receptor

Low tissue specificity; in the brain is mostly expressed in oligodendrocytes.

Human serum albumin-based NPs

[90] + HPA*

Choline

Endothelial cells of the BBB

Choline transporter (SLC5A7)

Tissue enriched: brain and intestine; in the brain is mainly expressed in endothelial cells and some subtypes of neurons.

Dendrigraft poly-L-lysin-based NPs

[91, 92] + HPA*

CRM197

Endothelial cells of the BBB

Neurons

Heparin-binding epidermal growth factor-like growth factor (HB-EGF)

Tissue enriched: urinary bladder;

increased in endothelial cells

PBCA

PLGA

[93] + HPA*

TGN

Endothelial cells of the BBB

N.T.

N.A.

PLA

[94]

VCAM-1 antibody

Endothelial cells of the BBB

VCAM-1

Tissue enriched: lymphoid tissue; increased in vascular endothelium and T-cells; in brain is mostly expressed in microglia.

Lipid nanoparticles

[95] + HPA*

ICAM1 antibody

Endothelial cells of the BBB

ICAM1

Tissue enriched: lung and urinary bladder; in the brain is mainly expressed in microglia.

Lipid nanoparticles

[95] + HPA*

Neurotensin

Neurons

Neurotensin receptor

Tissue enriched: intestine; in brain: 3-fold increased expression in neurons.

Graphene oxide NPs

[96, 97] + HPA*

Tet-1

Neurons

N.T.

N.A.

PEI

[98]

C4-3

Neurons

Tropomyosin receptor kinase B (TrkB)

Tissue enriched: skeletal muscle and tongue; in brain: 3-fold increased expression in neurons.

N.T.

[99] + HPA*

IKRG

Neurons

Tropomyosin receptor kinase B (TrkB)

Tissue enriched: skeletal muscle and tongue; in brain: 3-fold increased expression in neurons.

PCL

[100] + HPA*

Non-toxic carboxylic fragment of the tentanus neurotoxin

Neurons

N.T.

N.A.

Chitosan

PEI

[101,102,103]

Mel

kFGF

PasR8

Neurons, Astrocytes, Endothelial cells of the BBB

N.A.

N.A.

Liposomes

[104]

pVec

QL

TAT

Neurons, Astrocytes, Endothelial cells of the BBB

N.A.

N.A.

Liposomes

[105]

Glycoprotein g7

Neurons

Opioid receptor delta 1

Tissue enriched: brain; in brain: 6-fold increased expression in neurons.

PLGA

[106, 107] + HPA*

RVG (RVG-9r, RVG29)

Neurons

nAChR

Tissue enriched: adrenal glands and gastrointestinal tract; in the brain is increased in inhibitory neurons.

Liposomes

Human serum albumin-based NPs

[108, 109] + HPA*

AQP4 antibody

Astrocytes

AQP4 channel

Tissue enriched: brain and lung; in brain: specific marker of astrocytes.

PGMA

[110] + HPA*

D4 (GFAP) antibody

Astrocytes

GFAP

Tissue enriched: brain; in brain: specific marker of astrocytes.

Liposomes

[111] + HPA*

Bradykinin B2 antibody

Astrocytes

Bradykinin B2 receptor

Tissue enriched: urinary bladder; increased in excitatory neurons and glial cells.

Chitosan

[112] + HPA*

CD11b antibody

Microglia

CD11b (Integrin subunit α M)

Tissue enriched: bone marrow; increased in brain and immune system tissues; brain marker of microglia and macrophages.

Ceria-zirconia

[113] + HPA*

NG-2 antibody

Oligodendrocyte progenitor cells

NG-2 receptor

Tissue enriched: intestine; increased in the brain, namely in oligodendrocyte progenitors.

PLGA

[114] + HPA*

Myaptavin-3064

Oligodendrocytes

N.T.

N.A.

Streptavidin

[115]

LJM-3064

Oligodendrocytes

N.T.

N.A.

Exosomes

[116]

QTRFLLH

VPTQSSG

Neural progenitor cells

N.T.

N.A.

Wild-type adenoviral capsid

[117, 118]

NFL-TBS.40–63

Neural stem cells

N.T.

N.A.

Lipid nanocapsules

[119, 120]

Transferrin

Neural stem cells

N.T.

N.A.

Gold NPs and gold nanorods

[121]