Table 1.

Summary of drug delivery strategies to bypass the BBB

	Method	Description	Notes	Ref
Direct therapeutic administration to the CNS	Convection enhanced delivery (CED)	Infusion catheter inserted intracranially delivers therapeutics directly to the brain	Physically bypasses the BBB but procedure is invasive	[36–39]
	Intrathecal delivery	Injection of therapeutics into the CSF via the spinal canal	Enables drug delivery to spinal cord as well as brain	[58–60]
Temporary physical disruption of BBB	MRI-guided focused ultrasound (MRgFUS)	Focused ultrasound induces cavitation of IV administered microbubbles and temporarily permeabilizes BBB; MRI enables spatiotemporal control	Has been used in the clinic for thermal coagulation of tumors in human patients	[46, 48, 49]
Strategies to cross BBB after IV therapeutic administration and/or to penetrate brain ECM	Cell-based therapeutics	IV injected mesenchymal stem cells (MSCs) have been shown to cross the BBB and home to sites of brain tumor or injury. Engineered CAR T Cells and macrophages can be used to target and treat brain cancer	MSCs can be genetically engineered to secrete therapeutic molecules or molecules can be attached to the surface of MSCs	[61, 64, 65, 67, 68]
	Ligands targeting transferrin receptor	Transferrin receptor (TfR) is highly expressed by brain capillary endothelial cells, and ligands such as TfR-binding antibodies and the transferrin molecule can enable BBB crossing	Molecules that bind with ultra-high affinity to TfR have been shown to facilitate lysosomal sequestration in BBB endothelial cells and reduce transcytosis to the brain	[69, 73, 75]
	Angiopep-2 peptide	Angiopep-2 targets low-density lipoprotein receptor-related protein-1 (LRP1) that is expressed on brain endothelial cells lining the BBB	Angiopep-2 is also overexpressed on GBM and brain metastases from lung and skin cancers, enabling dual targeting of the BBB and cancer cells	[77–79]
	Sugar molecules	Glucose transporter protein 1 (GLUT1) on BBB endothelial cells allow drug delivery vehicles displaying ligands such as glucose or galactose to transport across BBB	Surface density of sugar molecules and rapid glycemic intake following fasting play an important role on nanocarrier transcytosis of the BBB	[81–84]