Abstract: Although nano-drug delivery systems have been carrying the high expectations to realize enhanced therapeutic effect with reduced toxicity, their in vivo efficacy is often significantly different from the results of in vitro study. With a major fraction of the administered dose distributing in the organs with abundant accumulation of macrophages, e.g. liver and spleen, the improvement in drug efficacy is very limited and toxic and side effects may occur in these organs as well. Therefore, prolonged half-life of drugs and decreased unwanted accumulation in non-target sites are of great significance to the clinical translation of nano-formulations. This review mainly focused on the effects of related organs such as liver and spleen on the delivery of nanoparticles, and the recent progress in the strategies of designing and constructing long-circulating nano-carrier systems, so as to provide reference for related researches.