CD24-targeted cystine and glucose oxidase cascade catalytic nanosystem triggers disulfidptosis in neuroblastoma

Neuroblastoma remains a challenging pediatric malignancy with limited therapeutic options, often complicated by chemoresistance and severe systemic toxicity. In this study, we developed a CD24-targeted nanodrug delivery platform that co-delivers cystine and glucose oxidase (GOx) to induce disulfidptosis in neuroblastoma cells. We engineered exosome-mimetic vesicles (EM-CD24) by transfecting HEK-293T cells with a plasmid encoding an anti-CD24 nanobody fused to a glycosylphosphatidylinositol (GPI) anchor signal derived from decay-accelerating factor (DAF), followed by sequential extrusion to obtain EMs with native exosome-like properties and scalable production potential. These vesicles display surface anti-CD24 nanobodies, enabling tumor-specific targeting. Our findings revealed that while cystine promotes cell growth under normal conditions, it induces disulfidptosis under glucose-deprived conditions. Leveraging this metabolic duality, we developed a redox-responsive nanoplatform, Cys-hMnO 2 @GOx@EM-CD24, by co-loading cystine and GOx into hollow MnO 2 nanoparticles and encapsulating them within EM-CD24 vesicles. CD24-mediated targeting significantly enhanced drug accumulation at the tumor site, reduced NADPH levels, and triggered cystine-induced disulfidptosis. This strategy markedly suppressed both primary and metastatic tumor growth with minimal systemic toxicity. Our findings highlight the efficacy of CD24-guided delivery and demonstrate the translational potential of exploiting tumor metabolic vulnerabilities through environment-responsive nanotherapeutics. • Identified CD24 as a novel therapeutic target in neuroblastoma and developed CD24-targeted engineered exosome mimetics. • We uncovered a context-dependent metabolic duality of cystine: it supports tumor cell proliferation under normal glucose levels but provokes robust disulfidptosis when glucose is limited. • Demonstrated the potential of combined glucose oxidase and cystine treatment to induce disulfidptosis in tumor cells. • Developed an in vivo applicable nanoplatform(Cys-hMnO 2 @GOx@EM-CD24) for precise co-delivery of glucose oxidase and cystine, which effectively induces disulfidptosis and suppresses tumor growth and metastasis both in vitro and in vivo.