Xiao‐Ting Xie

Cuproptosis is an emerging mode of programmed cell death for tumor suppression but sometimes gets resisted by tumor cells resist under specific mechanisms. Inhibiting copper transporter ATPase (ATP7A) was found to disrupt copper ion homeostasis, thereby enhancing the effect of cuproptosis and eventually inhibiting tumor invasion and metastasis. In this study, we develop a multifunctional nanoplatfrom based on Cu9S8 (CAPSH), designed to enhance cuproptosis in tumor cells by specifically targeting ATP7A interference, while combining thermodynamic therapy with immune effects. The release of copper ions from CAPSH and the copper homeostasis interference by siRNA cooperatively increases the concentration of copper ions in tumor cells, which induces effectively cuproptosis and activates immune responses for suppressing development and metastasis of tumor. This nanoplatform simultaneously regulates cuproptosis from both principles of onset and development, facilitating the application of cuproptosis in tumor therapy. Cuproptosis is an emerging mode of programmed cell death for tumor suppression but limited by the copper ion regulatory mechanisms in most tumor cells. Here, this group develops a Cu9S8-based nanoplatform for breast cancer-targeting and cuproptosis-induction via ATP7A interference, thereby eliciting thermodynamic cancer therapy.

Chemodynamic therapy (CDT) is widely explored for tumor-specific therapy by converting endogenous H2O2 to lethal ·OH to destroy cancer cells. However, ·OH scavenging by glutathione (GSH) and insufficient intratumoral H2O2 levels seriously hinder the application of CDT. Herein, we reported the fabrication of copper ion-doped ZIF-8 loaded with gold nanozymes and doxorubicin hydrochloride (DOX) for the chemotherapy and CDT synergistic treatment of tumors with the assistance of tumor microenvironment (TME)-activated fluorescence imaging. The Cu2+-doped ZIF-8 shell was gradually degraded to release DOX and gold nanoclusters responding to the acidic TME. The fluorescence signal of the tumor region was acquired after the quenched fluorescence of the gold nanoclusters by Cu2+ and DOX by aggregation-induced quenching was turned on because of the interaction of GSH with Cu2+ and the release of free DOX. The Cu2+ ions could deplete the GSH via redox reactions and the generated Cu+ could convert internal H2O2 to ·OH for tumor CDT. The chemotherapeutic effect of DOX was strengthened through drug efflux inhibition and drug sensitivity increase due to the consumption of GSH and ·OH burst. Moreover, DOX could raise the level of H2O2 and augment the effect of CDT. In addition, the fluorescent gold nanoclusters not only served as a peroxidase to convert H2O2 to ·OH but also employed as an oxidase to consume GSH, resulting in the amplification of chemotherapy and CDT. This work presents an approach to construct tumor microenvironment-activated theranostic probes without external stimuli and to achieve the tumor elimination through cascade reactions and synergistic treatment.

Plant-derived nanovesicles (PDVs) as nanodrug delivery carriers have gained recognition due to their satisfactory biosafety. However, there remains a challenge to target tumor sites accurately due to the uncertain membrane protein components on the surface of vesicles. Herein, a composite nanodrug delivery system by encapsulating the chemotherapy drug DOX is establish to efficiently target breast cancer. The novel nanoplatform (LEVBD) is formed by embedding the membrane fragments from breast cancer cell with the lemon-derived nanovesicles (LEVs) as the foundational skeleton. LEVBD reveal wonderful homologous tumor targeting due to fusion of cancer cell membrane components with LEVs, and the encapsulation of hybrid vesicles facilitates the transcellular transport of drugs. After intravenous injection, LEVBD could efficiently and selectively home to homologous tumor sites even under competition from heterologous tumors and significantly inhibit tumor growth without any observable toxic side effects. The doping of homologous cancer cell membranes provides a paradigm for the precise delivery of drug delivery vehicles using plant-derived vesicles as the backbone.