Table 3.

Strategies to harness transcytosis for brain‐targeted delivery

Strategies	Method		Challenges	Ref.
Exosome‐based	Non‐functionalization	Secreted from stem cells, macrophage, monocytes, mesenchymal stromal cells, dendritic cells, and cancer cells	Limited understanding of the BBB penetration mechanism; production of sufficient quantities; increasing efficiency in loading and BBB penetration	[176, 178, 179, 180, 181, 182]
	Functionalization	Targeting specific cells: e.g., RVG exosomes		[180, 186]
Nanoparticle‐based	Single functionality	Glucose/glucose transporter GLUT1	Biocompatibility, specificity (exclusively expressed on BBB cells); efficiency (high transport capacity); minimizing interference With the natural function of receptor or carriers;	[ 188 ]
		Angiopep‐2/LRP1		[ 189 ]
		Basigin antibody/basigin		[ 190 ]
		CD98hc antibodies/CD98 heavy chain		[ 190 ]
		Transferrin/transferrin receptor		[55, 191, 192, 193]
		Dopamine receptor		[ 194 ]
	Multi‐functionality	Crosslinked zwitterionic polymer/CXCL13		[ 195 ]
		Bispecific antibody		[167, 190, 196, 197]
		Multiple therapeutic cargos (e.g., a hydrophobic drug and a hydrophilic drug)		[ 198 ]
Virus‐based	Naturally existed	AAV9,AAV rh.10 and rh.8	Increasing transduction efficiency in brain endothelial cells; robust safety assessment; production of sufficient quantities; reduction in autoimmunity risks	[ 199 ]
	Engineered	AAV‐PHP.B		[ 200 ]