Chalcogen-bond engineered redox-responsive nano-prodrugs for anticancer therapy

The distinct redox imbalance in malignant cells, characterized by elevated reactive oxygen species and glutathione levels compared to normal tissues, establishes a therapeutic window for chemotherapeutic intervention through exploitation of the tumor microenvironment. Group 16 elements (sulfur, selenium, and tellurium) exhibit redox-modulating capabilities and engage in diverse biological processes, render them strategic candidates for developing tumor-selective nano-prodrugs that minimizing off-target toxicity. This review specifically focused on sulfur- (thioether, disulfide, and polysulfide), selenium, and tellurium-based nano-prodrugs constructed by linking small molecules-rather than polymeric or proteinaceous frameworks. We systematically examined structural determinants (chains length, substituent type, functional group composition) governing colloidal stability, chemical stability, and in vivo antitumor efficacy of these supramolecular assemblies. The strategic molecular engineering of linker motifs and side-chain architectures enhances drug delivery precision and therapeutic indices were also highlighted. Furthermore, we evaluate current translational progress in redox-responsive nano-prodrug platforms and propose rational design principles to advance their clinical translation, emphasizing structure-activity relationships and microenvironment-responsive drug release mechanisms.