Table 2.

Properties of non-viral vectors that affect their transport to the brain

Property	Mechanism and example
Targeting ligand	See details in Sect. 3 in this review
Ligand density	Ligand density substantially affects the brain accumulation of non-viral vectors. For example, Kataoka et al. reported a synthetic micelle system conjugated with different densities of glucose (0, 10, 25, and 50%, mol%) with 25% exhibiting the highest brain accumulation of the micelle [27]
Stimuli-responsiveness	Internal stimuli such as pH (endosomal pH at 5.5–6.5) [28, 29] and GSH (cytosolic GSH concentration at 1–10 mM) [30–33] have been used to facilitate nanoparticle disassembly/degradation in the brain cells and thus the release of payloads. External stimuli such as ultrasound [34–36] have been used to temporarily disrupt the BBB and/or enhance the brain accumulation of the non-viral vectors
Size	Previous studies found densely PEGylated nanoparticles with diameters ≤ 100 nm can exhibit faster spreading and larger diffusion volume in the mouse brain parenchyma in vivo after intracranial injections, compared to their counterparts with larger diameters. However, even so, the diffusion distance of the nanoparticles was still very limited in the brain parenchyma, typically around 1 mm surrounding the injection site. [37, 38]
Surface Charges	After intravenous administration, cationic nanoparticles are rapidly cleared with the shortest half-life, followed by anionic nanoparticles, whereas neutral and slightly negative charged nanoparticles have the longest half-lives in circulation [39]. Moreover, it is reported that PEGylated or negatively charged surface can help nanoparticle diffusion in the brain [37, 40, 41]
Shape	Most non-viral vectors are spherical, but shape affects the interaction of nanoparticles with cells [2]. Mitragotri et al. reported rod-shaped particles exhibited higher BBB transport than sphere-shaped ones in an in vitro BBB model [42]

GSH Glutathione, PEG Polyethylene glycol