Omeprazole-mediated nanodelivery of copper for synchronous remodeling of copper influx and efflux in cuproptotic glioblastoma therapy

Cuproptosis, a recently identified copper-dependent cell death modality, has opened a new territory in tumor therapy, which is promising to reverse the problem of chemoradiotherapy resistance due to its independence on the apoptotic mechanism. However, the inefficient promotion of copper influx and the intrinsic mechanism of copper efflux due to intracellular copper homeostasis significantly limit the efficacy of Cuproptosis. Herein, we propose a strategy to disrupt copper homeostasis by designing copper-omeprazole supramolecular nanodrugs (Cu-OME SNDs), which simultaneously promote copper influx and inhibit efflux, thereby leading to intense Cuproptosis. On the one aspect, OME coordinates with copper ions to form self-delivery SNDs, facilitating the influx of copper ions. Under the glutathione stimulation of tumor microenvironment (TME), Cu-OME SNDs disassemble and release cuprous ions, which bind with mitochondrial acyltransferases to initiate Cuproptosis. On the Other aspect, the released OME inhibits copper efflux by suppressing ATPase copper transporting alpha expression, further enhancing copper dyshomeostasis and potentiating Cuproptosis. A glioblastoma model is adopted to verify the Cuproptosis efficacy of Cu-OME SNDs. To improve the permeability across blood-brain tumor barrier (BTB), minoxidil sulfate (MS) and T7 peptide are modified on Cu-OME SNDs to produce Cu-OME/MS@T7 SNDs. T7 peptide actively targets the Transferrin Receptor, facilitating the accumulation of SNDs in glioblastoma sites. MS, serving as a molecularly targeted ATP-sensitive potassium (K_ATP) modulator, selectively boosts BTB permeability. Upon entering glioblastoma cells, the released MS further activates K_ATP channels, promoting SNDs accumulation and establishing a positive feedback loop. Additionally, the Cuproptosis induced by SNDs triggers immunogenic cell death in tumor cells, amplifying specific antitumor immunity and mitigating the immunosuppressive TME. Collectively, our findings demonstrate the effectiveness of OME-mediated nanodelivery of copper in inducing copper dyshomeostasis and triggering Cuproptosis, highlighting their considerable therapeutic promise through synchronous remodeling of copper influx and efflux. STATEMENT OF SIGNIFICANCE: Cuproptosis has opened a promising frontier in tumor therapy. However, its efficacy is substantially hampered by the inefficient copper influx and the intrinsic copper efflux mechanism driven by intracellular copper homeostasis. To address these challenges, we propose a "two birds with one stone" strategy to disrupt copper homeostasis using copper-omeprazole supramolecular nanodrugs (Cu-OME SNDs). In this design, OME coordinates with copper ions to form self-delivery SNDs, enhancing the delivery efficiency of exogenous copper ions. Meanwhile, the released OME further blocks copper efflux by suppressing ATP7A copper efflux transporter. Collectively, this work demonstrates the effectiveness of OME-mediated copper delivery in inducing copper dyshomeostasis and triggering Cuproptosis, highlighting a promising therapeutic approach through synchronous remodeling of copper influx and efflux.

Copper dyshomeostasis; Copper efflux; Copper influx; Cuproptosis; Glioblastoma; Omeprazole.