Pathophysiological conditions associated with cancer are also characterized by the presence of certain specific enzymes and/or abnormal levels of enzyme expression, 57 which stimulisensitive polymer prodrugs can also take advantage of. An interesting strategy, therefore, is to use the flexibility of RDRP to design polymer prodrugs incorporating enzymatically cleavable drug linkages. In this context, common families of enzymes have been often targeted as they are specific to tumor activities, as demonstrated for the proteases and hydrolases superfamilies. For example, a well-known and often targeted subfamily of hydrolases are esterases. Different types of esterases exist and differ in their biological targets and functions, as well as in a variable level of expression that could be dysregulated in the tumoral environment. It has also been reported that the stereoselectivity of some esterases can be affected in cancer cells, resulting in preferential hydrolysis of ester bonds. 114 Thus, hydrolysis of ester bonds appears to be a relevant tumor-targeting strategy via the design of ester linker-containing polymer prodrugs. The family of proteases is also often targeted when designing drug delivery systems. For example, cathepsin B-derived proteases are interesting targets for drug linkers because they could be used both as a tumor biomarker and for enzymatic cleavage activity. Another major protease known for its involvement in tumor-associated mechanisms belongs to the family of extracellular matrix mellatoproteinases that have been implicated not only in cancer cell migration, but also in the regulation of cell growth and angiogenesis. Proteases are able to hydrolyze amide bonds that are introduced in drug-based conjugates using peptide units as linkers that represent another interesting Esterases can also be used to degrade not the polymer-drug linker itself, but the polymer nanocarrier used to protect the drug from early degradation and to better expose it once the site of action is reached for improved therapeutic effect. This has been achieved with poly(lactide)-block-poly(2-hydroxyethyl acrylate-co-2-chloroethyl methacrylate) (PLA-b-P(HEA-co-CEMA)) diblock copolymers obtained by sequential ROP and RAFT polymerizations (Figure ), which were functionalized with a ruthenium-based metallodrug (RAPTA-C), known to be highly toxic in vitro and selective for metastases in vivo. Selfassembly of the copolymer prodrugs led to 250 nm-micelles exhibiting RAPTA-C drug moieties at their periphery. They showed complete disassembly when incubated with hydrolases for 2 days at 37 °C, mediated by the degradation of the PLA blocks. The micelles demonstrated a 10-fold increase in cytotoxicity on three ovarian cancer cell lines (A2780, A2780cis, and Ovcar-