# Stimuli-Responsive Polymeric Nanosystems for Controlled Drug Delivery
## 1 Introduction  
The progress of nanotechnology in the 21 st century has tremendously promoted the Nanomedicine development, leading to pharmaceutical improvements and healthcare enhancements. The nanoparticle systems that are predominantly developed for drug delivery are liposomes, nanomocelles, dendrimers, nanocrystals, and polymeric nanoparticles [1; 2; 3; 4; 5]. In particular, owing to their good biocompatibility and high designability, polymer-based nanoparticles have been extensively employed as drug delivery nanocarriers. Moreover, the biostability of polymeric nanosystems seems to be better than other nanocarriers, such as liposomes, and the delivery features can be manipulated by engineering the polymer composition and structure. A lot of polymers including natural and synthetic ones such as polycaprolactone and chitosan have been explored as building blocks for nanocarriers development. In particular, due to their good biocompatibility, availability, and FDA approved status, poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA) are the most extensively studied polymers. The PLGA- and PLA-based nanocarriers are easy to synthesize, and have been investigated for the delivery of many therapeutic agents [6; 7; 8]. Unfortunately, the drug encapsulated in these nanoparticles can be released in a relatively rapid speed (more than 50% release in 10 to 48 h) in both lesions and normal tissue [9]. The lack of spatiotemporal control over the nanosystems in determining where and when the loaded drug is released can significantly compromise the merits of these nanomocelines [10; 11]. To this end, the capability to modulate the drug release activity of nanocarriers by using specific triggers including both exogenous and endogenous stimuli can largely overcome the weakness of these conventional carriers and confer spatiotemporal control over their drug release. The last few years have witnessed tremendous progress in designing stimuli-responsive drug delivery nanocarriers to improve their tumor specificity when administered systemically [12]. A variety of stimuli-responsive polymeric nanocarriers that assemble or disassembly in response to endogenous stimuli such as pH [13], GSH [14] and protease [15; 16] or exogenous stimuli such as light [17], temperature [18] and ultrasound [19] have been developed for controlled drug release at the right site and time. For example, capitalizing on the slightly acidic microenvironment in tumor tissue in comparison to physiological condition (pH 7.4) in normal organs, pH-responsive nanocarriers have been designed for pH-triggered drug release at tumor site selectively [20; 21; 22; 13; 20]. The highly hypoxic tumor microenvironment that contains over 4-fold higher levels of reducing glutathione (GSH) than normal tissues is the advantage to develop GSH-responsive polymeric drug delivery systems [23; 24; 25; 14; 26]. In addition, owing to the overexpression of many proteases in cancer and their key roles in tumor progression, a number of protease-responsive polymeric nanosystems have been developed by integrating polymer materials with peptide modules to impart the nanoparticles with protease-selectivity, allowing for protease-unlocked drug release at tumor sites [27; 28; 29; 16]. On the other hand, the nanoparticles that can be triggered by exogenous stimuli enable the spatiotemporal control over the drug release through a remote equipment [30]. For example, light, especially near infrared (NIR) light, has frequently been exploited as stimulus to trigger the drug release of some well-designed polymeric nanosystems both in vitro and in vivo [31; 32; 33; 34]. A variety of nanoparticles that are sensitive to temperature have been designed for thermo-controlled drug release based on thermo-sensitive polymeric materials such as poly(\(N\)-iso-propylamide) (PNIPAAm) [35; 36; 37]. Ultrasound is also a widely explored stimulus for activatable polymeric drug delivery nanocarriers development due to the non-invasiveness and deep tissue penetration [38; 39; 40].