TABLE 2.

Ligands used for nanoparticles, for the transportation of neurotrophic factors through the blood–brain barrier.

Strategy	Ligand	Example	Effect; administration route*	References
Targeting of transferrin receptor	TfR antibody (OX26)	PEG-BDNF-OX26	Restoration of CA1 region in hippocampus after ischemia in rats in vivo; i.v.	Wu and Pardridge, 1999
Targeting of transferrin receptor	Transferrin	PEG-Liposomes with BDNF gene-transferrin	Increased immunoreactivity of BDNF in cerebral cortex of rats compared to the background; i.v.	Xing et al., 2016
Targeting of lactoferrin receptor	Lactoferrin	PEG-PAMAM-GDNF-lactoferrin	Dose-dependent improvement in locomotor activity and reduced loss of TH+ neurons in SN of 6-OHDA-treated rats; i.v.	Huang et al., 2009
Targeting of LRP-1 receptor	Angiopep (19 aa)	Dendrigraft poly-L-Lys-PEG-GDNF gene-angiopep	Improved locomotor activity and recovery of dopamine neurons in rotenone rat PD model	Huang et al., 2013
Conjugation of NTF to cell penetrating peptide (CPP)	TAT (11 aa)	TAT-GDNF	Increased number of viable neurons in the striatum after ischemia; i.v.	Kilic et al., 2003
Conjugation of NTF to CPP	TAT	TAT-GDNF	TAT-GDNF fusion protein reached dopamine neurons but did not increase the number on TH+ neurons in mouse MPTP model; i.v.	Dietz et al., 2006
Bypassing of BBB	None	PEG-PLE-BDNF NPs	Active BDNF was released upon interaction with its receptors, minimizing potential side effects. Increased level of BDNF-containing NPs accumulated in the brain (compared to native BDNF) in all studied brain regions, except for midbrain. Delivery route not specified.	Jiang et al., 2018
Bypassing of BBB; Conjugation of NTF to CPP	TAT	Chitosan-TAT-GDNF	Increased number of viable TH+ neurons, decreased number of Iba-1 cells in MPTP-treated mice; i.n.	Hernando et al., 2018
Transient microbubbles (MB)-induced BBB opening	Ultrasound-responsive MB inducing transient opening of the BBB	MB-Liposomes with GDNF gene MB-Liposomes with BDNF gene MB-Liposomes with BDNF and GDNF genes	Improvement of behavioral deficits and rescued dopamine neuron loss in MPTP mice in GDNF, BDNF and GDNF+BDNF groups; i.v.	Lin et al., 2016, 2020
Magnetic resonance–guided transient BBB opening	Ultrasound-responsive MB inducing transient opening of the BBB	MB-PEG- polyethylenimine-GDNF gene	Localized delivery of GDNF to striatum; 11-fold increase in striatal GDNF in 6-OHDA-treated rats. 2.2-fold increase in DA levels, 3.2-fold increase in dopamine cell number in the SNpc and 5-fold increase in TH+ fiber density in the striatum at week 12 in 6-OHDA-treated rats. i.v.	Mead et al., 2017

* i.n. – intranasal delivery, i.v. – intravenous delivery.