Nanotechnology for Neuroscience: Promising Approaches for Diagnostics, Therapeutics and Brain Activity Mapping.

2. Properties of Nanomaterials for Neuroscience The CNS is a highly guarded sanctuary, which complicates the diagnosis and treatment of CNS disorders. The blood-brain barrier (BBB) prevents larger molecules from penetrating the brain. [ 11 ] This restricted anatomical access makes diagnosis and treatment more difficult compared to other disease sites. Consequently, drug treatment of CNS disorders via systemic administration is often inefficient. The heterogeneous cellular and molecular environment, complex anatomical and functional “wiring”, and complicated information processing further add to this challenge. [ 12 ] In response to these difficulties, an increasing number of groups are investigating the properties of various nanomaterials to exploit the inherent advantages of their nanosize. Several essential properties and factors that make nanomaterials ideal for neuroscience are discussed in this section. Nanomaterials reflect the surface properties of organic tissues, such as topography and energy, more accurately than their conventional, micrometer-scale counterparts. Furthermore, due to their small size and advancements in synthesis methods, nanomaterials have many advantageous traits, such as high surface area-to-volume ratio, multi-functionality, site-specific delivery or targeting, controlled release and versatility in enabling surface modification. [ 13 ] These traits could help enhance the resolution and sensitivity of diagnostics, minimize side effects through targeted therapy and regulate therapeutic effects by controlling drug release in a specific environment. Therefore, nanomaterials can be used as vectors for drug delivery, as strategies for neuroprotection, as scaffolds for neuroregeneration and differentiation, as modalities for neuroimaging and as devices for neurosurgery. [ 14 ] Recently different types of nanomaterials (organic/inorganic NP systems) ( Figure 2 ) have been used in the field of nanoneuroscience, and their potential applications have been governed. [ 15 ] The structural and functional properties of these nanomaterials and their potential clinical applications in neuro-science are summarized in Table 2 . Multifunctional nanoparticles (MFNPs) have massively evolved as a new research area that can be tailored to possess specific functionalities and therapeutic solutions. [ 73 ] The diversity of structures in which MFNPs can participate is huge, as reflected by the ever-growing pool of nanomaterials with unique conductive, thermal, mechanical and toxicological properties. [ 74 ] These MFNPs can take the form of porous or non-porous and spherical or filamentous structures. Despite the wide variety of materials and structures used to construct MFNPs, they generally share similar principles. [ 74 ] A typical schema of a MFNP might involve an imaging domain such as a fluorescent probe, a targeting molecule such as a targeting ligand to bind to receptors expressed on cells, and a molecule to be delivered such as a drug or gene. [ 75 ] These components functionalize the NPs, hence the name “multifunctional nanoparticle”, and can be either embedded within a porous matrix or chemically bonded ligands that are readily functionalized upon integration with the target system. [ 76 ] Given the wide array of biophysical properties and core material combinations available and the number of structural permutations a given NP may assume, MFNPs can theoretically cure a large range of diseases in any biological environment in a site-specific and cell-targeted fashion. Shape is an important factor that has a substantial impact on drug delivery in terms of pharmacokinetics and BBB penetration, with a factor-of-10 difference in half-lives between spherical and filamentous nanomaterials. [ 77 ] Hence, nanomaterial shape is a critical factor when choosing a vector. The system into which nanomaterials are introduced also plays a key role in governing the dynamics of cell-particle interactions and, as a result, toxicological effects. Numerous studies have already demonstrated that biological agents, particularly microbial species, can influence nanomaterial stability either antagonistically or, in some instances, cooperatively. [ 78 ] Awareness of system-particle interactions is particularly important in the therapeutic context, as MFNPs are likely to be introduced into systems in a pre-existing disease state. Although content formulations impact structural properties, biological properties are more strongly influenced by surface chemistry, which is not always straightforward to analyse. Nonetheless, expanding our knowledge of the pharmacodynamics and pharmacokinetic properties of such interactions may facilitate the development of a platform for the future technologies, which will likely rely heavily on influencing native biological function itself by directing neuronal growth or affecting stem cell differentiation. No one MFNP system is ideal, as the properties of a NP depend on a combination of factors including surface functionalization, formulation, shape, size and the environment in which the NP is introduced. These considerations must be included when designing MFNP systems.

3.1. Potential Applications of Nanomaterials for Drug Delivery to the Central Nervous System The BBB restricts the entry of the majority of small molecules and macromolecules into the CNS. [ 11 ] This renders traditional systemic administration of most drugs ineffective. However, the applications of nanotechnology to drug delivery have been widely studied in vitro and in preclinical assessments and provide alternatives for the treatment of CNS disorders. Currently, there are four main ways to deliver drugs to the CNS: i) invasive delivery; ii) pharmacological approach (free passive movement of drugs across the BBB due to their small molecular size, low hydrogen bonding capacity and low lipophilicity, e.g., reduction of the number of polar groups, which increases drug transfer across the BBB; [ 79 ] iii) temporary disruption of the BBB; and iv) nanobased drug delivery systems. [ 80 ] Invasive delivery is only reserved for selected cases and is not efficient against brain metastases or neurodegenerative diseases, which require therapeutic agents to be delivered throughout the brain. [ 11 ] The reversible opening of the BBB via osmotic or chemical strategies does allow therapeutics to cross the BBB but can result in significant damage to the brain. [ 81 ] A less invasive option is the systemic administration of drug delivery systems to penetrate the vasculature of the brain. This can be achieved by using nanomaterials as transporters or carriers to improve lipid solubility and mask any drug properties that prevent crossing of the BBB. [ 82 ] NPs such as nanoliposomes, micelles, nanogels and dendrimers are examples of some technologies that have been employed for this purpose. Nanoliposomes are perhaps some of the earliest nanomaterials engineered for drug delivery. [ 83 ] These vesicles are composed of an aqueous core and one (unilamellar) or several (multilamellar) lipid or phospholipid bilayers. Conventional liposomes are cleared from the circulation via the reticuloendothelial system (RES). However, the circulation time can be extended through particle size reduction (