Red blood cells: The metamorphosis of a neglected carrier into the natural mothership for artificial nanocarriers

Drug delivery research pursues many types of carriers including proteins and other macromolecules, natural and synthetic polymeric structures, nanocarriers of diverse compositions and cells. In particular, liposomes and lipid nanoparticles represent arguably the most advanced and popular human-made nanocarriers, already in multiple clinical applications. On the other hand, red blood cells (RBCs) represent attractive natural carriers for the vascular route, featuring at least two distinct compartments for loading pharmacological cargoes, namely inner space enclosed by the plasma membrane and the outer surface of this membrane. Historically, studies of liposomal drug delivery systems (DDS) astronomically outnumbered and surpassed the RBC-based DDS. Nevertheless, these two types of carriers have different profile of advantages and disadvantages. Recent studies showed that RBC-based drug carriers indeed may feature unique pharmacokinetic and biodistribution characteristics favorably changing benefit/risk ratio of some cargo agents. Furthermore, RBC carriage cardinally alters behavior and effect of nanocarriers in the bloodstream, so called RBC hitchhiking (RBC-HH). This article represents an attempt for the comparative analysis of liposomal vs RBC drug delivery, culminating with design of hybrid DDSs enabling mutual collaborative advantages such as RBC-HH and camouflaging nanoparticles by RBC membrane. Finally, we discuss the key current challenges faced by these and other RBC-based DDSs including the issue of potential unintended and adverse effect and contingency measures to ameliorate this and other concerns.