Rational Design of Cancer Nanomedicine for Simultaneous Stealth Surface and Enhanced Cellular Uptake

Owing to the complex and still not fully understood physiological environment, the development of traditional nanosized drug delivery systems is very challenging for precision cancer therapy. It is very difficult to control the in vivo distribution of nanoparticles after intravenous injection. The ideal drug nanocarriers should not only have stealth surface for prolonged circulation time but also possess enhanced cellular internalization in tumor sites. Unfortunately, the stealth surface and enhanced cellular uptake seem contradictory to each other. How to integrate the two opposite aspects into one system is a very herculean but meaningful task. As an alternative drug delivery strategy, chameleon-like drug delivery systems were developed to achieve long circulation time while maintaining enhanced cancer cell uptake. Such drug nanocarriers can "turn off" their internalization ability during circulation. However, the enhanced cellular uptake can be readily activated upon arriving at tumor tissues. In this way, stealth surface and enhanced uptake are of dialectical unity in drug delivery. In this review, we focus on the surface engineering of drug nanocarriers to obtain simultaneous stealth surfaces in circulation and enhanced uptake in tumors. The current strategies and ongoing developments, including programmed tumor-targeting strategies and some specific zwitterionic surfaces, will be discussed in detail.