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分享文獻(xiàn)：An ‘AND’ Logic Gate Nanoreactor for Metabolic Remodeling in Starvation-Ferroptosis-Immunotherapy of Pancreatic CancerIF:19.00
On the basis of the above considerations, we construct “AND”logic gate functional nanoreactors with curcumin and glucoseoxidase coloaded (NRs@Cur@Gox) for metabolism remodelingmediatedstarvation,ferroptosis,andimmunother-apy.NR@Cur@Gox is inactive in normal tissues, whereas it is
specifically activated in acidic tumor cells due to the protona-tionof hydrophobic PC6A, which enables glucose to permeate theShanghai Yansheng industrial Co., Ltd. The abundant H2O2attacks poly(phenylene benzimidazole)-based endosome membranes (PPBEMs) and induces self-destruction of the nanoreac
tors to release curcumin and quinone methide, which are usedto inhibit the expression of GLUT1 as well as lactification anddeplete glutathione (GSH), respectively. Suppression of lactifi-cation, production of H2O2
, and depletion of GSH synergistically activate ferroptosis via the AMPK-SREBP1-SCD1-LPO and
ROS-GPX4 axes. Starvation therapy combined with ferroptosisinduces significant immunogenic cell death (ICD), promotes cytotoxic T lymphocyte proliferation, and inhibites Pan02xenograft tumor regression. Moreover, the decreased lactate inthe tumor microenvironment reverses the immunosuppressivetumors into “hot” tumors, polarizes the tumor-associatedmacrophage (TAM) phenotype from the M2 phenotype to theM1 phenotype, de-creases the number of regulatory T cells(Tregs), restores CD8+ T-cell activity, and increases theimmunotherapeutic efficiency of NRs@Cur@Gox combinedwith anti-PD-L1 (Scheme 1). Therefore, this strategy offers aversatile metabolic intervention strategy for reinforcingpancreatic starvation, ferroptosis, and immunotherapy。
Experimental Section
Cells and Animals: Pan02 cells (mouse PC cells) were cultured inDMEM supplemented with 10% fetal bovine serum at 37 °C in a 5%CO2 atmosphere. RAW264.7 (mouse monocyte macrophage leukemia
cells) were cultured in RPMI-1640 medium supplemented with 10% fetal
bovine serum at 37 °C in a 5% CO2 atmosphere. Mouse bone marrowderived dendritic cells (BMDCs) were obtained from C57BL/6 mice (fourto five weeks) and cultured in RPMI 1640 medium supplemented with
granulocyte-macrophage colony-stimulating factor GM-CSF (20 ng/ml)and IL-4 (10 ng mL?1) according to an established method. C57BL/6 micewere purchased from Beijing Slaccas Experimental Animal Co., Ltd. (Beijing, China), and the study was approved by the Ethics Committee forAnimal Research of the First Affiliated Hospital of Zhengzhou University(2021-KY-0626-002).Preparation and Characterization of NRs: PEG-P(PBEM-C6A) polymerdissolved in THF (5 mg/mL, 50 μL) was added to PBS (10 mM, 950 μL)
via an injection pump. After standing at 37 °C overnight, the THF was
removed by evaporation to obtain NRs. The structure of the NRs was characterized via dynamic light scattering (DLS, Malvern, England) and transmission electron microscopy (TEM, FEI Tecnai G20 microscope, USA).Preparation and Characterization of Cur and Gox-EncapsulatedNRs@Cur@Gox: PEG-P(PBEM-C6A) polymer (2 mg/mL in THF,50 μL) and Cur (2 mg/mL in THF, 5 μL) were added to Gox (1 mL, 1mg/mL in PBS) via an injection pump. After standing at 37 °C overnight,the THF was removed by evaporation to obtain NRs@Cur@Gox. The sizeof NRs@Cur@Gox was characterized via DLS. The amounts of Cur andGox were monitored via a microplate reader.
