The tumor accumulation of nanomedicines relies on the enhanced permeability and retention
(EPR) effect. In the last 5-10 years, it has been increasingly recognized that there
is a large inter- and intra-individual heterogeneity in EPR-mediated tumor targeting,
explaining the heterogeneous outcomes of clinical trials in which nanomedicine formulations
have been evaluated. To address this heterogeneity, as in other areas of oncology
drug development, we have to move away from a one-size-fits-all tumor targeting approach,
towards methods that can be employed to individualize and improve nanomedicine treatments.
To this end, efforts have to be invested in better understanding the nature, the complexity
and the heterogeneity of the EPR effect, and in establishing systems and strategies
to enhance, combine, bypass and image EPR-based tumor targeting. In the present manuscript,
we summarize key studies in which these strategies are explored, and we discuss how
these approaches can be employed to enhance patient responses.