Endogenous stimuli-responsive intelligent drug delivery systems: recent advances in cleavable linker design

Controllable drug release at target sites represents an important challenge in precision medicine. With advances in chemistry, materials, and biology, novel stimuli-responsive systems are being designed and fabricated for applications in biomedicine and pharmaceuticals. Endogenous biochemical signals, such as specific enzymes, pH, redox, and other species, provide natural targets for the development of stimuli-responsive intelligent drug delivery systems (DDSs). This review deeply analyzes the cleavable linkers that utilize these signals to trigger drug release. We explore the molecular design principles, chemical cleavage mechanisms, structure-activity relationships, and the applications (e.g. antibody-drug conjugates, prodrugs, and nanocarriers) of these linkers. Furthermore, the article explores novel linker strategies for addressing tumor heterogeneity and drug resistance, and outlines the challenges and future directions for their application in delivering emerging therapeutic drugs.