Controlled drug delivery with nanoassemblies of redox-responsive prodrug and polyprodrug amphiphiles

Self-assembled nanostructures are highly promising for controlled delivery of therapeutic and diagnostic agents. However, for conventional drug delivery nanosystems, there exist some intrinsic limitations such as low drug-loading contents, premature and burst release, nanocarrier matrix-associated toxicity and immunogenicity, and poor shelf stability. To address these issues, the covalent integration of active drug molecules into prodrug and polyprodrug amphiphiles and fabrication of self-delivery nanomedicines via controlled molecular self-assembly have emerged as a new paradigm. Moreover, it is crucial to achieve on-demand and selective activation of prodrugs and polyprodrugs in a spatiotemporally controlled manner, thus considerably reducing the occurrence of systemic toxicities. In this context, dynamic variations of reductive/oxidative (redox) milieu across normal and pathological tissues, cells, and cytoplasmic compartments provide accessible biochemical stimuli for triggered release of intact drugs. In this review, we highlight recent progresses on emerging applications of redox-activatable nanostructures self-assembled from prodrug and polyprodrug amphiphiles.