Design of nanocarriers based on complex biological barriers in vivo for tumor therapy

Abstract Nanoscale drug delivery systems (NDDS) have shown great potential in tumor treatment due to its unique advantages, especially its unique enhanced permeability and retention effect (EPR) in solid tumors. Therefore, NDDS have been extensively explored in recent years. However, current NDDS did not achieve satisfied clinical therapeutic effect against to tumor treatment. This is mainly ascribed to two reasons. One is that nanocarriers would inevitably encounter a series of physiological and pathological barriers in vivo , leading to low drug transport efficiency. The other is that tumor stroma pose a huge obstruction to tumor therapy, nanotherapeutics just focus on the tumor cells themselves are insufficient for complete tumor eradication. Here in this review, we first outlining sequential biological obstacles encountered by nanocarriers from three levels of blood, tumor tissue and tumor cells. Then, we give a detailed discussion of the role of tumor stroma, and highlight the therapeutic resistances mediated by tumor stroma. In light of these formidable barriers, we provide promising approaches to overcome each barrier or remodel stroma through innovative NDDS design. Finally, we give proposals and considerations of NDDS design, and then discuss several existing challenges and further opportunities of NDDS in clinical application. This review seeks to provide guidelines for optimizing NDDS design through mitigation of biological barriers to efficient tumor therapy.