SLC7A11-independent disulfidptosis induced by a two-pronged delivery strategy for bladder cancer chemotherapy and cisplatin-resistance reverse

The intracellular overload of disulfide is induced by the imbalance between cystine (Cys) uptake and intracellular Cys reduction, leading to disulfidptosis. Solute carrier family 7 member 11 (SLC7A11) is a Cys transporter at the cell surface, and its high level of expression, together with glucose deprivation, is a requisite determining the disulfidptosis induction. Recent studies have exploited glucose deprivation by multifunctional nanomaterials as mainstream to evoke disulfidptosis, unfortunately with a strong bias to SLC7A11 highly expressed tumors. Despite many efforts to modulate SLC7A11 expression, the uncertainty brought by complex biological mechanisms under different exposure inspired us to find a more solid approach to raise Cys-uptake efficiency. In this study, we developed a two-pronged approach to deplete glucose and enrich intracellular Cys by co-biomineralizing Cys, glucose oxidase (Gox), and manganese as one entity, further cloaked with tumor cell membrane (M@Cys-Gox-Mn) to enhance tumor-selective uptake. M@Cys-Gox-Mn nanoparticles (NPs) displayed no SLC7A11-dependence for Cys transport and their synergistic action of the dual enzymes enables self-amplifying glucose depletion, thus exacerbating the disulfide stress. The use of M@Cys-Gox-Mn NPs as monotherapy greatly combat orthotopic bladder tumors, and the combination with cisplatin overcome the chemoresistance. Both therapies achieved complete tumor inhibition with favorable biosafety.