Overcoming the Reticuloendothelial System Barrier to Drug Delivery with a "Don't-Eat-Us" Strategy

Overcoming the reticuloendothelial system (RES) has long been a vital challenge to nanoparticles as drug carriers. Modification of nanoparticles with polyethylene glycol helps them avoid clearance by macrophages but also suppresses their internalization by target cells. To overcome this paradox, we developed an RES-specific blocking system utilizing a "don't-eat-us" strategy. First, a CD47-derived, enzyme-resistant peptide ligand was designed and placed on liposomes (D-self-peptide-labeled liposome, DSL). After mainline administration, DSL was quickly adsorbed onto hepatic phagocyte membranes (including those of Kupffer cells and liver sinusoidal endothelial cells), forming a long-lasting mask that enclosed the cell membranes and thus reducing interactions between phagocytes and subsequently injected nanoparticles. Compared with blank conventional liposomes (CL), DSL blocked the RES at a much lower dose, and the effect was sustained for a much longer time, highly prolonging the elimination half-life of the subsequently injected nanoparticles. This "don't-eat-us" strategy by DSL was further verified on the brain-targeted delivery against a cryptococcal meningitis model, providing dramatically enhanced brain accumulation of the targeted delivery system and superior therapeutic outcome of model drug Amphotericin B compared with CL. Our study demonstrates a strategy that blocks the RES by masking phagocyte surfaces to prolong nanoparticle circulation time without excess modification and illustrates its utility in enhancing nanoparticle delivery.