This diagram presents a protein network within the BL, which affects the diffusion of NCs that cross the BBB toward brain parenchyma, with smaller NCs being more efficient in crossing the network compared to larger NCs, which may be trapped in the protein network.

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The treatment of brain diseases is challenging partly due to the inaccessibility of therapeutic agents to the brain.

There is a notion that the permeability of the bloodbrain barrier (BBB) increases with aging or disease, however, the body has a defense mechanism that still retains the separation of the brain from harmful chemicals in the blood.

This makes drug delivery to the diseased brain, even more challenging and complex task.

Here, the physiological changes to the diseased brain and aged brain are covered in the context of drug delivery to the brain using nanoparticles.

Also, recent and novel approaches are discussed for the delivery of therapeutic agents to the diseased brain using nanoparticle based or magnetic resonance imaging guided systems.

Furthermore, the complement activation, toxicity, and immunogenicity of brain targeting nanoparticles as well as novel in vitro BBB models are discussed.

As research in this area has expanded, several of the issues that might increase the likelihood of success or prevent creation of a new therapy have become clearer.

In this review, we seek to describe the biological, physiological, and physical background to some of these with the intention of encouraging those working in this area at the same time as providing them with a map that highlights some of the pitfalls that must be avoided.

As a result, researchers have investigated methods to maintain or recover the BBB functionality such as the intravenous (i.v.) injection of mesenchymal stem cells (to inhibit the deterioration of BBB function), 7 oral administration of terflunomide (promoting pericyte coverage, pericyte survival and downregulating tight junction degradation), 8 or use of Panax notoginseng saponins (by activation of Nrf2 antioxidant defense system).

These approaches could improve the efficacy of drug delivery to the brain by NPs or NCs by restoring the BBB integrity.

Furthermore, the receptors involved in the normal functioning of the BBB may be dysfunctional in brain diseases.

Finally, the physiological environment of the brain may change due to chemicals or diseases.

Technological innovations have provided researchers with new tools to study the BBB and these are beginning to also include variations that reflect the changes in the BBB in disease states but gaps are highlighted by our comprehensive survey such as models for the aging BBB.

The BBB achieves this partly by shielding the neural cells from harmful agents in the blood, but this protective role of the BBB makes drug delivery to the brain more challenging compared to other organs, where blood capillary fenestration facilitates delivery of the drug molecules to the target cells.

To overcome the BBB, NPs and NCs have been developed, which cross the BBB by mechanisms such as receptor mediated transcytosis (RMT), a process inherent to normal functioning brain endothelial cells.

Figure 1 presents a transmission electron microscopy (TEM) image of a normal human neurovascular unit.

The tight junction (TJ) is presented as an electrondense elongated line, with the basal lamina (BL) encompassing an endothelial cell (EC), surrounded by pericytes, but with gaps in the BL, with astrocyte endfeet located behind.

The total surface area of microvasculature is 12 m 2 in the adult brain, which corresponds to 100 cm 2 g 1 of brain tissue.

The total length of capillaries in the brain is about 650 km.

These capillaries are typically 40 m apart and the capillary lumen diameter is about 6 m.

TJs are formed between two overlapping separate impermeable cell membranes, one on the inside of the vessel wall (luminal side) and the other on the outside (abluminal side).

Hence, the TJ is a slant cut rather than a straight short cut from the luminal side to the abluminal side.

Typically the gap is between 300 and 500 nm between the luminal side and abluminal side of brain microvessels.

Reproduced with permission.

P: pericyte, BL: basal lamina, EC: endothelial cell, A: astrocyte, TJ: tight junction.

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