GSH-triggered CD44/FRβ dual-targeting nanoprodrug for acute myeloid leukemia eradication via cascade DNA damage and mitochondrial oxidative storm

• Etoposide and Olaparib combination triggered a synergistic 'DNA damage-repair blockade' cascade effect that overcame AML drug resistance. • The GSH-responsive dual-targeting nanoprodrug allowed AML-specific drug delivery and activation while significantly reducing systemic toxicity. • Intracellular drug release induced a mitochondrial oxidative storm, synergistically propelling apoptosis. • HA-FA@Etp-Olp markedly enhanced in vivo antitumor efficacy without observable organ toxicity. Conventional DNA double-strand breaks (DSBs)-inducing chemotherapeutics for acute myeloid leukemia (AML) are often limited by poor solubility, non-selectivity, and drug resistance stemming from robust tumor DNA repair mechanisms. Here, we report a glutathione (GSH)-responsive, dual-targeting nano-prodrug, designated HA-FA@Etp-Olp, for efficient AML cell eradication. The HA-FA@Etp-Olp system was constructed through the conjugation of the PARP inhibitor Olaparib (Olp) with Etoposide (Etp) via a disulfide linkage, forming an Etp-Olp heterodimeric prodrug. This hydrophobic conjugate was encapsulated within a polymeric carrier composed of poly (ethylene glycol)-modified hyaluronic acid (HA) functionalized with folic acid (FA), self-assembling into well-refined nanoparticles. Exhibiting excellent circulatory stability, HA-FA@Etp-Olp achieved efficient accumulation within AML cells leveraging CD44/FR dual-receptor-mediated active targeting, followed by GSH-triggered disassembly and specific drug release in response to elevated intracellular GSH levels. Furthermore, HA-FA@Etp-Olp elicited a synergistic cytotoxic effect against AML through a dual-pronged mechanism: "DNA damage-repair blockade" cascade and significant augmentation of mitochondrial oxidative stress, effectively inducing apoptotic cell death. This strategy provides a promising targeted nanotherapeutic approach with enhanced efficacy and reduced systemic toxicity, demonstrating significant potential for the precise treatment of AML.