Table 2.

Pros and cons of different strategies to open the BBB

Strategies		Methods	Pros	Cons	Ref.
Transient disruption of BBB tight junctions	Chemical methods:	Osmotic agents (mannitol)	Clinic approved. Rapid onset of action (within 5 to 10 min after administration) which results in opening the BBB to a wide range of substances	Short half‐life and side effects, such as inducing seizures and increasing intracranial pressure	[139, 140, 141, 142]
		Angiogenic molecules (VEGFA)	Approved in the clinic	Non‐specific opening of the BBB, which may cause side effects	[ 35 ]
		S1P	Broad effects, including regulation of brain endothelial cell junction, transcytosis, and efflux transporter activity	Dose‐sensitive	[143, 144]
		S1PR1 modulator: Fingolimod	Approved in the clinic	Size‐selective opening of the BBB, Controversial effects on BBB integrity	[97, 145]
		Autoantibodies (GRP78)	Opening of the BBB to macromolecules	Inflammation‐induced BBB breakdown may be harmful
	Physical method:	MR‐FUS	Highly efficient, enables focus on targeted region, promising results in multiple clinical trials	Sensitive to ultrasound intensity, may cause side effects such as chronic inflammation	[33, 146, 147, 148]
Overcoming efflux transporters		Inhibitors of P‐gp and BCRP1	Some inhibitors are approved in the clinic	Mixed results in clinical studies. Potential side effects as P‐gp and BCRP1 are critical for metabolism and excretion of cytotoxic agents from the brain.	[132, 134, 149, 150]