Stimulus-cleavable chemistry in the field of controlled drug delivery

Stimulus-cleavable nanoscale drug delivery systems are receiving significant attention owing to their capability of achieving exquisite control over drug release via the exposure to specific stimuli. Central to the construction of such systems is the integration of cleavable linkers showing susceptibility to one stimulus or several stimuli with drugs, prodrugs or fluorogenic probes on the one hand, and nanocarriers on the other hand. This review summarises recent advances in stimulus-cleavable linkers from various research areas and the corresponding mechanisms of linker cleavage and biological applications. The feasibility of extending their applications to the majority of nanoscale drug carriers including nanomaterials, polymers and antibodies are further highlighted and discussed. This review also provides general design guidelines to incorporate stimulus-cleavable linkers into nanocarrier-based drug delivery systems, which will hopefully spark new ideas and applications.