The mechanisms of nanoparticle delivery to solid tumours

Nanoparticles for the detection and treatment of cancer have suffered from limited clinical translation. A key problem has been the lack of understanding of the mechanisms of nanoparticle delivery to solid tumours. The current delivery mechanism is called the enhanced permeability and retention effect, which states that nanoparticles passively enter the tumour through gaps between endothelial cells and are retained because of poor lymphatic drainage. However, nanoparticles designed according to the enhanced permeability and retention effect have limited delivery to solid tumours. An alternative mechanism proposes that nanoparticles enter the tumour through active endothelial transport processes, are retained in the tumour due to interactions with tumour components and exit the tumour through lymphatic vessels. This mechanism is called the active transport and retention principle. In this Review, we explore the contrasting views of these two mechanisms of nanoparticle delivery to solid tumours, explaining the underlying biological mechanisms and their effect on nanoparticle design for cancer applications. Defining the nanoparticle delivery mechanisms to solid tumours is crucial to the advancement and clinical translation of cancer nanomedicines and to determining how nanoparticles should be engineered for medical use. The mechanisms of nanoparticle delivery to solid tumours guide the engineering of nanoparticles for cancer applications. This Review discusses two contrasting nanoparticle delivery mechanisms, the enhanced permeability and retention effect and the active transport and retention principle, and their implications for the design of cancer nanomedicines.