 Abstract nanomedicines are attractive paradigms to deliver drugs, contrast agents, immunomodulators, and gene editors for cancer therapy and diagnosis. However, the currently developed nanomedicine suffers from poor serum stability, premature drug release, and lack of responsiveness. To address these issues, cross-linking strategy can be employed to tightly hold the nanostructure and release the payload spatio-temporally in a highly controlled manner. This review summarizes recent innovations in stimuli-responsive cross-linked nanomedicines, SCN, which have been designed to circumvent the drawbacks of the conventional drug delivery system. The SCNs are categorized according to the type of cross-linkage, including built-in, on-surface, and interparticle cross-linkages. Stimuli-responsive cross-linkages enable the nanomedicines to maintain robust stability during systemic circulation, while also allowing them to respond to the particular tumoral conditions, resulting in improved drug delivery efficiency, tumour targeting ability, and imaging sensitivity. This article was authored by Shandong Zhu, Hai Jing Chu, and Yuan Pei Li. We are article.tv, links in the description below.