Targeting disulfidptosis: from molecular mechanisms to nanotechnology-mediated delivery strategies

Disulfidptosis is a metabolism-dependent programmed cell death driven by nicotinamide adenine dinucleotide phosphate (NADPH) depletion, ultimately leading to aberrant disulfide bond accumulation and cytoskeletal collapse. This pathway offers a novel paradigm for the selective targeting of solute carrier family 7 member 11 (SLC7A11)-high tumor cells. In this review, we systematically compile the repertoire of disulfidptosis-inducing agents and categorize them according to three distinct mechanisms: direct inhibition of the SLC7A11 transporter, interference with glucose uptake or NADPH generation, and disruption of the cystine-glutathione redox balance. Critically, while these small-molecule and macromolecular agents exhibit promising activity, their clinical translation is severely constrained by poor aqueous solubility, inadequate tumor specificity, and systemic toxicity. To address these barriers, we synthesize recent advances in nanotechnology-enabled delivery systems and provide a mechanism-based framework for combined nanotherapies centered on disulfidptosis. These strategies integrate disulfidptosis induction with metabolic regulation, other programmed cell death modalities (cuproptosis, ferroptosis, and pyroptosis), physical energy-based therapies (radiotherapy, sonodynamic therapy, and photodynamic therapy), and immunotherapy, thereby amplifying metabolic vulnerabilities and converting immunologically cold tumors into hot ones. This review establishes a conceptual foundation for designing next-generation disulfidptosis-based nanomedicines and holds significant promise for advancing precision oncology strategies toward clinical implementation.