With unique potentials for organ drug delivery and targeting, intravenous administration of drugs has represented a key tool in
biomedicine. A major concern of this route is the rapid capture and destruction of foreign substances by circulating immune cells.
Knowledge about the inter-relationships between drugs and blood cells is essential for a better control in drug stability and bioavailability.
In this review, both classical pathways and novel insights into the immune mechanisms leading to drug clearance after systemic delivery
are described. Drug surface chemistry and size have been identified as critical factors for the activation of host immune responses,
and their modification has been extensively explored in order to evade immune surveillance. Common strategies to camouflage drug surfaces
through polymer-grafting are presented, with special emphasis on Poly(Ethylene Glycol) (PEG) linkages, one of the most diverse
strategies for modifying biomolecular surfaces. Finally, the use of “smart shields”, such as PEG attachments shed at particular intracellular
conditions, is briefly overviewed as an interesting approach for balancing circulation half lives VS bioavailability in polymer-grafted
Keywords: Engineered nanoparticles, PEGylation, drug metabolism, innate immunity, immune response to nanoparticles, drug clearance,
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