# Stimuli-Responsive Polymeric Nanosystems for Controlled Drug Delivery
## 3 Stimuli-Responsive Polymeric Nanosystems
### Endogenous Stimuli-Responsive Polymeric Nanosystems  
#### 3.1.1 Enzyme-Responsive Polymeric Nanosystems  
Enzymes, proteins with catalytical activities, play critical roles in the regulation of almost all physiological processes [102, 103, 104]. The aberrations of enzymes activity have been implicated in a variety of diseases [103]. In particular, a variety of enzymes such as proteases are frequently overexpressed in cancers and have been recognized as biomarkers of tumors [27, 105, 106]. Besides their biomarker role in malignancies, most enzymes can catalyze the chemical reactions in a mild condition in comparison to the harsh conditions of many traditional chemical reactions [107]. Additionally, the enzymes show high specificity to their substrates, allowing for selective chemical reactions catalyzed by enzymes [108]. The last decade has witnessed great progress in developing stimuli-responsive drug delivery nanocarriers controlled by tumor-overexpressed enzymes such as proteases [109]. Proteases, the enzymes that degrade proteins by catalyzing the hydrolysis of peptide bonds, are frequently dysregulated in pathologies. A lot of proteases such as matrix metalloproteinases (MMPs) and cathepsin B (CatB) are overexpressed in tumors, and they are widely recognized as biomarkers for tumor diagnosis and therapy [27, 105]. The peptide substrates that can be specifically recognized by tumor-overexpressed proteases such as MMP2/9 and CatB have been widely employed to design protease-responsive polymeric drug delivery systems, [110, 111, 28, 112] and several of them are in clinical trials [113, 114, 112]. Considering the key role proteases play in tumorigenesis, progression, and metastasis, the advantages of protease-triggered drug delivery systems are high speci \begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Name of Polymer** & **Applications** & **Stimuli** & **Benefits** & **Drawbacks** & **References** \\ \hline PCL & Drug delivery, tissue engineering & Heat, pH & Multifunctional adjustability & Low degradation rates and solubility & [41, 42, 43, 44, 45, 46] \\ PLGA & Drug delivery & Heat & Ease of synthesis, hydrolyzable & Low biocompatibility & [8, 47, 48, 49, 50, 51, 52] \\ Poly(amides) & Drug delivery & Enzyme, ROS & Cheavability by enzymes & Cytotoxicity & [53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69] \\ POEs & Surgical sutures, drug delivery & pH, light & Acidity control & Highly hydrophobicity & [70, 71, 72] \\ PEAs & Drug delivery & Enzyme, US & High programmability & Biocompatibility & [73, 74, 75, 76, 77, 78, 79] \\ Poly(phosphoesters) & Drug delivery & Enzyme & Convolutional adjustability & Synthesis complexity & [80, 81, 82, 83, 84, 85] \\ Natural polymers & Drug delivery, tissue engineering & Enzyme, pH & Good biocompatibility & Programmability & [86, 87, 88, 89] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Polymers for drug delivery applications. ficity and efficacy. In one case, [PERSON] et al. developed a smart drug delivery nanosystems by masking the positive charges on low molecular weight protamine with a polyanionic peptide (E10) via a MMP-2/9-hydrolyzable peptide linker sequence (Pro-Leu-Gly-Leu-Ala-Gly, PLGLAG) to obtain an activatable low molecular weight protamine (ALMWP, E10-PLGAAG-VSRRRRRRGGRRRR) [115]. The ALMWP was further conjugated to PEG-PCL drug delivery nanosystems to enhance the tumor accumulation and treatment efficacy of the nanoformulation. Apart from MMPs, cathepsins are the other useful class of proteases that have drawn great interest in developing a variety of stimuli-responsive nanomicelles for drug delivery applications. The past decades have witnessed great progress in designing and constructing a range of cathepsin-responsive polymeric drug delivery systems, which are predominantly engineered by introducing a tetra-peptide module (Gly-Phe-Leu-Gly, GFLG) that can be specifically cleaved by CatB to polymeric materials [116; 117]. The pioneering work of [PERSON] et al.