Tumor-targeted nanomedicines have been extensively applied to alter the drawbacks and enhance the efficacy of chemotherapeutics. Despite the large number of preclinical nanomedicine studies showing initial success, their therapeutic benefit in the clinic has been rather modest, which is partially due to the inefficient tumor penetration caused by tumor microenvironment (high density of cells and extracellular matrix, increased interstitial fluid pressure). Furthermore, tumor penetration of nanomedicines is significantly influenced by physicochemical characteristics such as size, surface chemistry and shape. The effect of size on tumor penetration has been exploited to design nanomedicines with switchable size to tackle this challenge. Moreover, several pharmacological and physical approaches have been developed to enhance the tumor penetration of nanomedicines, by penetration-promoting ligands, intratumoral drug release, and modulating the tumor microenvironment and vasculature. Overall, these efforts have resulted in nanomedicines with better tumor penetration properties and with enhanced therapeutic efficacy. Future research should be directed to penetration-promoting strategies with broad applicability and with high translational potential.

Nanomedicine and macroscale materials are increasingly impacting cancer immunotherapy.