Charge-reversal nanocarriers: An emerging paradigm for smart cancer nanomedicine

The surface charge of nanoparticles (NPs) plays an essential role in determining their biological properties both in vitro and in vivo. In view of the complex features associated with the biological or physiological microenvironment of solid tumors, such as electrostatic interactions between NPs and serum components, cellular membrane, or intracellular organelles, drug-loaded NPs (or nanocarriers) should intelligently accommodate such unique extra- or intracellular microenvironment in order to achieve maximum therapeutic and/or diagnostic efficacy. To that end, the surface charge of nanocarriers needs to be readily converted at the target site by means of charge reversal, i.e., conversion from anionic to cationic, or vice versa, depending on specific microenvironment. In such a manner, the payloads could be efficiently released at the desired tumor site. This review discusses 1) the physicochemical aspects related to long-circulating nanocarriers for systemic applications; 2) the recent progress in charge-reversal nanocarriers, which are loaded with drugs, nucleic acids, proteins or imaging agents and triggered by various biological signals (i.e., pH, redox, ROS or enzyme) associated with tumor microenvironment, with an emphasis on those induced by acidic tumoral pH; and 3) the perspectives of charge-reversal nanocarriers regarding thorough investigations on how the chemical structure of charge-reversal moiety temporally affects the responsiveness of the resulting nanocarriers toward the rational design of precision cancer nanomedicine.