Advanced strategies for extending the blood circulation time of nano-based delivery systems

The rapid clearance of nano‑based delivery systems has motivated the search for strategies to extend the blood circulation time. This review moves beyond traditional strategies used for the design of extended blood‑circulation nanomaterials, and examines some recent advances in two complementary domains: physicochemical optimization and biological modulation. This review highlights trends in chemical and topological modifications regarding PEGylation, and shows that the transition to alternative polymers is accompanied by a set of challenges and advantages. It also examines various types of transformable nanoparticles and highlights the dangers inherent in stimulus heterogeneity and the complexity of their manufacturing process. The innovations and challenges of protein‑corona engineering are likewise evaluated. Furthermore, the modulation of complement and macrophage pathways as major immunological barriers promoting rapid NP clearance is discussed, and new approaches such as complement inhibitors and mononuclear phagocyte system blockade are explored. In addition, hitchhiking and biomimetic systems are discussed as emerging strategies to enhance blood circulation. Finally, we discuss the transition from static systems to dynamic, biointeractive, targeted and controllable platforms for achieving prolonged blood circulation.