A refined coadministration regime to mitigate immunological clearance of biomedical nanoparticles

Nanoparticles are frequently designed as carriers to mediate the active transport of their cargo to the site of action, thereby serving as effector particles. However, after their in vivo administration, they become quickly recognized by immune cells and are cleared from the systemic circulation. This significantly impairs the nanoparticles' targeting efficiency and shifts the target/off-target ratio toward metabolizing organs. As engineering-driven strategies, such as the PEGylation of their surface, require major modifications of the nanoparticles' structure and do not appear to achieve the desired level of effectiveness, synergistic approaches are attracting increasing attention. They rely on the transient blockade of the immune system through endocytosis inhibitors or decoy nanomaterials. In the present study, we introduce a further development of these synergistic approaches by loading lipid nanocapsules (LNCs) as decoy nanoparticles with the endocytosis inhibitor chloroquine. Two principal advantages can be ascribed to this refined synergistic approach: First, encapsulation of the endocytosis inhibitor paves the way for pioneering subcutaneous application as a novel route of administration for the effector nanoparticles, as phagocytic cells within the lymphatic system can be selectively targeted. Second, the established co-administration regime constitutes a transferable concept across diverse settings without the need for structural modifications of the respective effector nanoparticles. Here, we report the successful in vitro establishment of this refined coadministration regime. Preincubation with chloroquine-loaded LNCs led to a statistically significant uptake inhibition of model effector nanoparticles into macrophages. Moreover, we investigated, for the first time, the incorporation of 1,2-Dioleoyl-sn-glycero-3-phosphoserine as a macrophage-specific targeting structure into the decoy LNCs' envelope and its effect on the phagocytosis activity of macrophages.