# Stimuli-Responsive Polymeric Nanosystems for Controlled Drug Delivery
## 3 Stimuli-Responsive Polymeric Nanosystems
### Endogenous Stimuli-Responsive Polymeric Nanosystems
#### 3.1.3 Redox-Responsive Polymeric Nanosystems  
The uncontrolled proliferation of tumor cells is often associated with the redox difference between tumor cells and normal cells. For example, the high levels of reactive oxygen species (ROS) and glutathione (GSH) in tumor cells are considered as promising targets for construction of tumor-selective drug release nanosystems [131; 132]. H\({}_{2}\)O\({}_{2}\) is the most abundant ROS species in tumor cells due to its longer half-life than others, making it a potential target for preparation of ROS-responsive nanoplatforms [133]. To establish ROS-responsive systems, the polymers are often incorporated with arylboronic or thioketal esters. [PERSON] et al. reported an safe and efficient gene delivery polymeric material poly(amino thioketal) (PATK) with ROS responsibility synthesized through polymerization of oligoamines with acrylamide thioketal [134]. The polymer could be degraded by the high level of ROS in tumor cells, leading to the disassembly of DNA/PATK complexes and DNA release.  
GSH, a tripeptide composed of glycine, cysteine, and glutamate, is the other most explored redox stimuli in tumor cells for stimuli-sensitive nanocarriers development [135]. The integration of disulfide bond in polymers is the widely explored strategy for GSH-responsive nanosystem construction [136]. Of note, poly(disulfide), the intriguing disulfide-containing polymers synthesized through ring-opening disulfide exchange polymerization, are biodegradable GSH-responsive polymeric materials for intracellular delivery of a variety of drug agents including nucleic acids, proteins, and small molecular drugs [137; 138; 139; 140].  
Figure 4: Schematic diagram of AmB-loaded dual pH-responsive micelleplexes for siRNA delivery with enhanced siRNA endosomal escape ability. (**A**) Production of AmBloaded PDMA-b-PDPA micelleplexes. AmB was loaded in the hydrophobic PDPA core, and siRNA was complexed with the PDMA corona shell. (**B**) AmB-facilitated endosome disruption and siRNA cytoplasmic release (a: AmB-loaded micelleplexes dissociated in early endosomes after cell uptake, and AmB molecules are inserted into endosomal membranes; b: protonated PDMA-b-PDPA unimers complexed with siRNA and trafficked from early endosomes into late endosome/lysosomes, causing vesicle swelling; c: AmB-enhanced siRNA release from endosomes into cytoplasm via membrane destabilization). (**C**) In the case of AmB-free micelleplexes, polymer/siRNA complexes were entrapped in late endosomes or lysosomes without efficient cytoplasmic siRNA release. Reproduced from ref. [130] with permission from the American Chemical Society.  
Moreover, the disulfide linkers within poly(disulfide)s could improve the cytosol delivery through thiol-mediated cellular uptake, which bypassed endosomal and lysosomal entrapment and degradation. Most recently, [PERSON] et al. reported the poly(disulfide)s-based platform synthesized through copolymerization of diethylenetriamine moieties containing monomer 1 and guanidyl ligands containing monomer 2 for efficient cytosol delivery of both nucleic acids and proteins (Figure 5) [141]. The thiol-mediated uptake of the poly(disulfide)s-based nanoplatforms and the cleavage of disulfide linkers within poly(disulfide)s by the upregulated intracellular GSH contributes to its excellent delivery performance. Additionally, the degradation of the polymers by GSH in cytosol not only promoted the loaded cargo release but also avoided the cytotoxicity of the polymer accumulation in the cytosol.