Current Nanomedicine 2468-1881/16 $58.00+.00 © 2016 Bentham Science Publishers Nikolaos Naziris a , Natassa Pippa a,b , Stergios Pispas b,* and Costas Demetzos a a Department of Pharmaceutical Technology, Faculty of Pharmacy, Panepistimioupolis Zografou 15771, Na- tional and Kapodistrian University of Athens, Athens, Greece; b Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635, Athens, Greece A R T I C L E H I S T O R Y Received: May 28, 2016 Revised: June 23, 2016 Accepted: July 02, 2016 DOI: 10.2174/246818730666616071223 2449 Abstract: Responsiveness to environmental stimuli is a phenomenon that characterizes liv- ing cells and organisms and relates to fundamental principles of life. It is of great interest to understand this complicated and multifactorial mechanism, in order to build multifunctional biomaterials and devices, like drug nanocarriers. Based on this concept a number of impor- tant applications have arisen, using synthetic stimuli-responsive polymers that are exhibit- ing novel properties, in order to produce innovative responsive nanosystems. The nanocar- riers that are able to transport bioactive molecules to the target tissues are developed based on their ability to respond to the environmental stimuli found in living cells and human body. These bio-inspired nanosystems use their endogenous responsiveness sensors, which originate from the chemistry of the biomaterials that compose them. The nature and the properties of biomaterials (lipids, polymers etc) lead to appropriate biophysical behavior and compatibility with the human organism. External stimuli, like heat, light, magnetic or electric field and ultrasounds, as well as endogenous ones, such as temperature changes, pH variations, redox potential and ionic strength differences can affect the responsiveness of a bio-inspired drug delivery nanosystem and consequently, its effectiveness. Concerning the various drug nanocarriers that can be rendered stimuli-responsive, there are several classes, including liposomes, niosomes, lipoplexes and polymersomes, micellar delivery nanosys- tems, dendrimers, polymer-drug and polymer-protein conjugates. The scope of this work is to review the so far extensive research that has been conducted on the area of stimuli- responsive drug delivery nanosystems and to present the journey from bench to clinic. Keywords: Stimuli-responsive, nanocarriers, nanobiomaterials, bio-inspired, advanced drug delivery nanosystems, smart systems, nanotheranostics. 1. INTRODUCTION Stimuli-responsive nanosystems have, for a while now, been an important topic in Nanotech- nology, as they embody the modern scientific ef- fort to mimic responsivity of cells to external stimuli, which is a key component of the behavior of living systems. This innovative approach is *Address correspondence to this author at the Theoretical and Physical Chemistry Institute, National Hellenic Research Founda- tion, 48 Vassileos Constantinou Avenue, 11635, Athens, Greece; Tel: +30210-7273824; Fax: +30 2107273794; E-mail: pispas@eie.gr being tested and applied in many areas, like re- source and energy issues, with predominant appli- cations in biomedicine, for the delivery and release of bioactive components to pathological tissues and for imaging and diagnostic purposes. The technology of nanocarriers with stimuli-respon- sivity is based on the utilization of biofunctional nanomaterials, with the most popular being “smart” polymers, peptides and lipids, which can be natural or synthetic. These macromolecules, belonging to the class of soft materials, are bio- compatible and demonstrate stimuli-sensitive properties that may be exploited for modulatory Send Orders for Reprints to reprints@benthamscience.ae 166 Current Nanomedicine, 2016, 6, 166-185 REVIEW ARTICLE Stimuli-responsive Drug Delivery Nanosystems: From Bench to Clinic