Nanocarriers with tunable surface properties to unblock bottlenecks in systemic drug and gene delivery

Nanocarrier-mediated drug and gene delivery systems hold great promise for providing more refined delivery (especially in cancer treatments) to maximize therapeutic efficacy while minimizing unfavorable side effects. Despite their promise, the highly effective transport of therapeutics in vivo remains a challenge. Over the last 20years, there has been a large amount of research directed toward the development of a multitude of nanocarriers for drug and gene delivery, but only a very small part has progressed into clinical trials. This suggests that the properties of current nanocarriers are not yet ideal for effective drug and gene delivery in vivo. Nanocarrier-mediated drug and gene delivery is a multi-step process, and inefficient delivery at any stage would ultimately result in an unsuccessful delivery. Unfortunately, existing nanocarriers with fixed surface properties, such as a PEGylated, cationized and bioconjugated surface, are not versatile enough to overcome the extracellular and intracellular barriers which require different surface properties. Consequently, their delivery efficacy is not optimal, leading to doubts and debates on the value of nanocarrier-based product development. To resolve the "fixed surface dilemma", the switchable surfaces of nanocarriers, which can surmount both extracellular and intracellular barriers, open up the possibility of highly efficient delivery in vivo. Here, we review and highlight the recent developments in the design of nanocarrier delivery systems with tunable surface properties in response to microenvironment triggers. Strategies including zwitterionic nanocarriers, polymer brushes, layer-by-layer nanocarriers and cleavable conjugated nanocarriers are presented. These representative examples and their respective outcomes elaborate the benefits and efficiencies of these nanocarriers at the individual stages of drug and gene delivery.