The xenoparticle opsonisation by complement proteins, over 30 soluble and membrane-bound proteins, induces the complement activation through

a cascade of physiological events. The opsonisation finally promotes the removal process by phagocytes [4]. The complement is a key component of innate immunity that naturally monitors host invaders through three distinct activation pathways described in Figure 1 [6]. Figure 1 Schematic representation of the different activation pathways of the complement system. (Reprinted with permission from Biomaterials, 2006, 27, 4356–4373. Copyright ©2006 Elsevier Ltd.) The classical pathway is activated after Inhibitors,research,lifescience,medical the fixation of C1q proteins to antibodies or to C1q thereby receptors on the cell surface. The alternative pathway is spontaneously activated by the binding of Inhibitors,research,lifescience,medical C3 fragments to the surface of the pathogen. The lectin pathway is activated by the binding of mannose-binding lectin on mannose contained on the surface corona of bacteria and viruses. Although a few hypotheses have been proposed to explain the existence of supplementary activation pathways, they Inhibitors,research,lifescience,medical have not been fully elucidated. Regardless of the activation pathway, the enzymatic cascade of the complement activation leads to the formation

of a common enzyme, C3 convertase, which cleaves the central protein of the complement system, the third component C3 [7]. The fragment C3b of C3 is the crucial active component that triggers the cleavage of a variety of complement proteins (C5–C9). The assembly of these proteins contributes to the formation of the membrane attack complex (MAC) that

is able to destabilize bacteria, viruses, and nanocarriers for drug delivery. C3b and its inactive fragment Inhibitors,research,lifescience,medical iC3b can be recognised by specific receptors on phagocytic cells leading to the engulfing of opsonised particles and their removal from the bloodstream. Additionally, the complement activation triggers a cascade of Inhibitors,research,lifescience,medical inflammatory and adverse complex reactions, named complement activation-related pseudoallergy (CARPA), that reflect in symptoms of transient cardiopulmonary distress. These effects have been detailed by the literature [8–11]. The complement system is also Batimastat finely regulated by the presence of inhibitor proteins such as C1 INH, Factor I and H [12]. Even though the natural role of opsonisation is directed to the body sellectchem protection from xenogeneic nanosystems, this process promotes the removal of circulating drug nanocarriers. This represents a major obstacle to achieve adequate systemic and local therapeutic drug concentrations. 2.1. Steric Shielding and Stealth Properties of Nanocarriers In the bloodstream, opsonins interact with nanoparticles by van der Waals, electrostatic, ionic, and hydrophobic/hydrophilic forces. Therefore, the surface features of the nanocarriers have a key role in the opsonisation process.