Stealth and pseudo-stealth nanocarriers.

The stealth effect plays a central role on capacitating nanomaterials for drug delivery applications through improving the pharmacokinetics such as blood circulation, biodistribution, and tissue targeting. Here based on a practical analysis of stealth efficiency and a theoretical discussion of relevant factors, we provide an integrated material and biological perspective in terms of engineering stealth nanomaterials. The analysis surprisingly shows that more than 85% of the reported stealth nanomaterials encounter a rapid drop of blood concentration to half of the administered dose within 1 h post administration although a relatively long β-phase is observed. A term, pseudo-stealth effect, is used to delineate this common pharmacokinetics behavior of nanomaterials, that is, dose-dependent nonlinear pharmacokinetics because of saturating or depressing bio-clearance of reticuloendothelial system (RES). We further propose structural holism can be a watershed to improve the stealth effect; that is, the whole surface structure and geometry play important roles, rather than solely relying on a single factor such as maximizing repulsion force through polymer-based steric stabilization (e.g., PEGylation) or inhibiting immune attack through a bio-inspired component. Consequently, engineering delicate structural hierarchies to minimize attractive binding sites, that is, minimal charges/dipole and hydrophobic domain, becomes crucial. In parallel, the pragmatic implementation of the pseudo-stealth effect and dynamic modulation of the stealth effect are discussed for future development.