Overcoming the biological barriers in the tumor microenvironment for improving drug delivery and efficacy.

The delivery of drugs to tumors by nanoparticles is a rapidly growing field. However, the complex tumor microenvironment (TME) barriers greatly hinder drug delivery to tumors. In this study, we first summarized the barriers in TME, including anomalous vasculature, rigid extracellular matrix, hypoxia, acidic pH, irregular enzyme level, altered metabolism pathway and immunosuppressive conditions. To overcome these barriers, many strategies have been developed, such as modulating TME, active targeting by ligand modification and biomimetic strategies, and TME-responsive drug delivery strategies to improve nanoparticle penetration, cellular uptake and drug release. Although extensive progress has been achieved, there are still many challenges, which are discussed in the last section. Overall, we carefully discuss the landscape of TME, development for improving drug delivery, and challenges that need to be further addressed.