Recent progress on charge-reversal polymeric nanocarriers for cancer treatments

Nanocarriers (NCs) for delivery anticancer therapeutics have been under development for decades. Although great progress has been achieved, the clinic translation is still in the infancy. The key challenge lies in the biological barriers which lie between the NCs and the target spots, including blood circulation, tumor penetration, cellular uptake, endo-/lysosomal escape, intracellular therapeutics release and organelle targeting. Each barrier has its own distinctive microenvironment and requires different surface charge. To address this challenge, charge-reversal polymeric NCs have been a hot topic, which are capable of overcoming each delivery barrier, by reversing their charges in response to certain biological stimuli in the tumor microenvironment. In this review, the triggering mechanisms of charge reversal, including pH, enzyme and redox approaches are summarized. Then the corresponding design principles of charge-reversal NCs for each delivery barrier are discussed. More importantly, the limitations and future prospects of charge-reversal NCs in clinical applications are proposed.