Nanoscale size controllable and surface modifiable zeolitic imidazolate framework-8–poly(acrylic acid sodium salt) (ZIF-8–PAAS) nanocomposites are fabricated by employing PAAS nanospheres as a soft template. These ZIF-8–PAAS nanocomposites have different sizes ranging from 30 to 200 nm and exhibit different crystallinity, and pH sensitivity. These nanocomposites can be employed as vectors to deliver doxorubicin for anticancer therapy, leading to greatly enhanced drug therapeutic efficacy when tested in cell lines and mice model. Systematic toxicity investigation including hematoxylin and eosin staining analysis of tumor and major organs, hematology analysis, and blood chemistry analysis indicates that the nanocomposites possess high biocompatibility. This work provides a strategy to make metal–organic frameworks (MOFs) nanocomposites with size tunability in nanoscale and flexible surface modification for various applications.