Microenvironment-responsive drug delivery systems (DDSs) can achieve targeted drug delivery, reduce drug side effects and improve drug efficacies. Among them, pH-responsive DDSs have gained popularity since the pH in the diseased tissues such as cancer, bacterial infection and inflammation differs from a physiological pH of 7.4 and this difference could be harnessed for DDSs to release encapsulated drugs specifically to these diseased tissues. A variety of synthetic approaches have been developed to prepare pH-sensitive DDSs, including introduction of a variety of pH-sensitive chemical bonds or protonated/deprotonated chemical groups. A myriad of nano DDSs have been explored to be pH-responsive, including liposomes, micelles, hydrogels, dendritic macromolecules and organic-inorganic hybrid nanoparticles, and micron level microspheres. The prodrugs from drug-loaded pH-sensitive nano DDSs have been applied in research on anticancer therapy and diagnosis of cancer, inflammation, antibacterial infection, and neurological diseases. We have systematically summarized synthesis strategies of pH-stimulating DDSs, illustrated commonly used and recently developed nanocarriers for these DDSs and covered their potential in different biomedical applications, which may spark new ideas for the development and application of pH-sensitive nano DDSs.Copyright © 2022 Elsevier B.V. All rights reserved.