# Stimuli-Responsive Polymeric Nanosystems for Controlled Drug Delivery
## 3 Stimuli-Responsive Polymeric Nanosystems
### Exogenous Stimuli-Responsive Polymeric Nanosystems  
#### 3.2.1 Light-Responsive Polymeric Nanosystems  
Due to its high spatiotemporal controllability regarding the dosage, wavelength, time and space, light has emerged as a fascinating tool for controlling the drug release activity of polymeric drug delivery nanocarriers [33; 34]. To develop light-controlled drug release nanosystems, the most widely explored strategy is incorporation of photolabile or photoswitchable moieties in the polymers to impart light-responsive property to the building blocks.  
The past few decades have witnessed tremendous progress in developing UV light (340-380 nm) responsive polymers. Several functional moieties have been widely incorporated into polymers to endow them with physical or chemical changes upon being irradiated with UV light. Azobenzene can undergo photoisomerization upon UV light irradiation by transiting from trans to cis forms, and the transition can be reversed upon visible light (420-490 nm) irradiation. The UV light triggered conformational transition and the change in hydrophilicity of polymers led to the disassembly of the nanoplatforms established from the azobenzene incorporated polymers, and thus triggered the drug release [142]. [PERSON] et al. reported the UV light-responsive nanovesicles self-assembled from the 4-isobutyloxyazobenzene units (AZO) containing amphiphilic linear-dendritic block copolymers (LDBCs) [143]. Upon UV irradiation, the nanovesicles will be deformed and  
Figure 5: Schematic illustration of the preparation of poly(disulfide)s, the complexation of genome editing biomacromolecules (Cas9 plasmid, Cas9 mRNA, and Cas9 ribonucleoprotein) by poly(disulfide)s, and their intracellular delivery processes for genome editing. Reproduced from ref. [141] with permission from the American Chemical Society.  
the membrane permeability increased, leading to the release of encapsulated fluorescent molecules. In addition to azobenzene, spiropyran can also switch between hydrophobic closed form and hydrophilic open form after being irradiated with UV and visible light, respectively [144; 145]. Besides the photoisomerization of azobenzene and spiropyran in response to UV light irradiation, the coumarin, cinnamic ester, or cinnamic acid incorporated polymers can also respond to UV light through cross-linking of the polymers [146; 147]. Despite the progress made in developing UV light-responsive nanosystems, their biomedical applications are limited by the superficial tissue penetration depth of UV light and the cytotoxicity. Near-infrared (NIR) light (750-1000 nm) offers the advantages of deeper tissue penetration and lower photocytotoxicity, which makes it an appealing external stimulus to trigger the drug release of nanocarriers [148; 149]. [PERSON] et al. reported a NIR light-responsive nanoplatform for controlled cargo release by disrupting the block copolymer micelles (Figure 6) [150]. The nanoplatform was engineered by loading NaYF4:TmYb upconversion nanoparticles (UCNPs) and hydrophobic cargos into the poly(ethylene oxide)-block-poly(4,5-dimethoxy-2-nitrobenzyl methacrylate) copolymer micelles. Upon 980 nm light irradiation, the UCNPs would convert the NIR light to short wavelength UV light which could be absorbed by o-nitrobenzyl groups in the copolymer, leading to the photocleavage of the copolymer. Then, the encapsulated cargos would be released owing to the NIR light triggered disassembly of the micelles. The NIR light can also be utilized to trigger the payload release through photothermal effect based on gold nanorods that can act as NIR-to-heat nanotransducer. The drug release that is triggered by heat will be described in the following section.