Drug-loaded polymer nanoparticles are being extensively studied for use in a wide range of diseases, such as cancer. They are exclusively obtained by formulating pre-synthesized degradable polymers in the presence of drugs using emulsification methods such as nanoprecipitation or emulsification-solvent evaporation. Yet, this preparation process has significant shortcomings, such as the production of low-concentration nanoparticles with low drug loadings (typically 1-5 wt %) and the early and abrupt release of the drug postadministration (i.e., burst release), which induces prohibitive toxicity and reduces therapeutic efficacy. Compatibility problems between the drug and the polymer matrix may also arise, which can affect the colloidal stability of the nanoparticles. Some of these issues can be alleviated using polymer prodrugs (also called polymer drug conjugates), in which the drugs are chemically bound to the polymer. The resulting polymer prodrug nanocarriers generally exhibit sustained drug release and higher drug loadings, leading to greater therapeutic efficacy compared to the traditional drug-loaded counterparts. Nevertheless, these systems still require formulation methods based on preformed polymers for their preparation. There is therefore an urgent need to develop a robust two-in-one strategy to generate in situ degradable polymer prodrug nanoparticles for drug delivery applications.