Pulmonary metastasis and limited treatment tolerability remain major bottlenecks underlying the poor prognosis of high-risk Wilms' tumor (WT). Disulfidptosis, a recently defined metabolic cell-death modality driven by disulfide stress and characterized by F-actin cytoskeletal collapse, offers a new route to exploit tumor metabolic vulnerabilities; however, the therapeutic application of this concept is constrained by SLC7A11-associated metabolic heterogeneity and the impracticality of systemic glucose deprivation. Guided by the context-dependent metabolic effect of L-cystine in WT cells, we propose a “supply restriction–load increase” framework and develop a CD276-targeting cell-membrane-camouflaged biomimetic nanoplatform, (Bay/Cys)@hMnO₂@EM-CD276, to achieve lesion-enriched co-delivery of BAY-876 and L-cystine. Mechanistically, by inhibiting glucose uptake while increasing intracellular cystine/disulfide burden, the nanoplatform amplifies redox imbalance and disulfide stress, induces high-molecular-weight aggregation/smearing of cytoskeleton-associated proteins under non-reducing conditions, and causes pronounced F-actin disruption, consistent with disulfidptosis-associated phenotypes. Increased intracellular ROS levels and a decreased GSH/GSSG ratio further indicate perturbed redox homeostasis. In orthotopic WT and pulmonary metastasis models, this nanoplatform markedly suppresses tumor progression, reduces pulmonary metastatic burden, and prolongs survival without obvious systemic toxicity under the current dosing regimen. Collectively, this work provides a potential design principle for exploiting metabolic vulnerability through coordinated pathway stress and tumor-associated marker-guided biomimetic delivery, supporting metabolic synergistic therapy for high-risk WT.
Luo et al. (2026) studied this question.