Table 2.

Approaches for improving BBB crossing of nanoparticles.

Primary Method	Sub-Method	Description	References
Paracellular pathway	-	Ultrasound/microbubbles and osmotic pressure are two methods for disrupting tight junctions between neighboring endothelial cells, both of which increase BBB permeability locally, allowing nanoparticle entrance. However, when the BBB’s homeostatic role is lost, this strategy carries certain hazards, as it would enable uncontrolled entrance of various substances into the brain, potentially resulting in cerebral toxicity.	[182]
Transcellular diffusion	-	The simplest transcellular route involves passive diffusion through the cell membrane and cytoplasm. To cross the phospholipidic bilayer of the membrane, nanoparticles must be small enough and at least partially lipophilic.	[183]
Transcytosis pathway	Adsorptive transcytosis	The surface characteristics of the nanoparticles make it easier for the nanoparticle and its payload to attach to the endothelial cells’ luminal plasma membrane. Because the plasma membrane of endothelial cells is negatively charged, positively charged nanoparticles are more likely to undergo this process than neutral or negatively charged ones. Nanoparticles coated with wheat germ agglutinin, for example, may be taken up by nerve terminals and retrogradely transported to the CNS by axons.	[184]
	Receptor-mediated transcytosis	Where nanoparticles with various ligands on their surfaces can bind to certain receptors and so enhance endocytosis GLUT1, lactoferrin (Lf), transferrin (Tf), or other peptides such as angiopep-2 or Seq12 have all been employed as targets.	[185,186]
Endocytosis	Clathrin-mediated endocytosis	Endocytotic vesicles up to 200 nm in diameter are formed in clathrin-enriched portions of the cell membrane. Once within the cell, clathrin-coated vesicles fuse together to form an early endosome, which progresses to late endosomes when the intravesicular pH drops and, eventually, lysosomes, triggering cargo destruction. To be an effective delivery agent, the nanoparticle must make it easier for its payload to escape from endosomes before they merge with lysosomes, preventing cargo destruction.	[187]
	Caveolin-mediated endocytosis	This occurs in lipid rafts and results in plasma membrane invaginations of roughly 80 nm in size. Following this first stage, caveolin vesicles merge with other caveolin vesicles to form caveosomes, which evade lysosomes and have a variety of fates depending on the cell type.	[187]