Long circulating nanocarriers: achievements and shortcomings of biomimetic approaches

Adequate longevity in the systemic circulation is a prerequisite for many nanocarriers to fulfill their entrusted mission, be it an extended release of the incorporated drug or targeting of certain cells or tissues. This is, however, majorly challenged by the adsorption of the opsonins on the nanoparticle (NP) surface, creating a beckoning protein corona which promotes identification and clearance by the mononuclear phagocyte system (MPS). To this date, various approaches have been developed to endow NPs "stealth" properties, prolonging thereby their residence time in the blood flow. While control of NP size and surface modification with hydrophilic neutral moieties remain the most popular strategies to this end, literature has recently witnessed the advent of a diverse range of biomimetic approaches that reconcile the biological concepts with nanotechnological principles to endow nanocarriers decent circulation half-lives. The current review seeks to present an in-depth and comprehensive discussion of these strategies along with the advantages and shortcomings associated therewith. This is followed by a debate of the challenges that are to be overcome to facilitate the clinical and industrial translation of this platform, along with the necessary preclinical and clinical considerations for selecting a suitable approach.