Metal ions/nucleotide coordinated nanoparticles comprehensively suppress tumor by synergizing ferroptosis with energy metabolism interference

Abstract

Background Ferroptosis holds promise as a potential tumor therapy by programming cell death with a hallmark of reactive oxygen species (ROS)-induced lipid peroxidation. However, vigorous energy metabolism may assist tumors to resist oxidative damage and thus weaken the effects of ferroptosis in tumor treatment. Results Herein, a bifunctional antitumor platform was constructed via coordinated interactions between metal ions and nucleotides to synergistically activate ferroptosis and interrupt energy metabolism for tumor therapy. The designed nanoparticles were composed of Fe2+/small interfering RNA (siRNA) as the core and polydopamine as the cloak, which responded to the tumor microenvironment with structural dissociation, thereby permitting tumor-specific Fe2+ and siRNA release. The over-loaded Fe2+ ions in the tumor cells then triggered ferroptosis, with hallmarks of lipid peroxidation and cellular glutathione peroxidase 4 (GPX4) down-regulation. Simultaneously, the released siRNA targeted and down-regulated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in the tumor to inhibit glycolytic pathway, which interfered with tumor energy metabolism and enhanced Fe2+-induced ferroptosis to kill tumor cells. Conclusions This study presents a concise fabrication of a metal ion/nucleotide-based platform to integrate ferroptosis and energy metabolism intervention in one vehicle, thereby providing a promising combination modality for anticancer therapy. Graphical Abstract

GAPDH Is a Novel Ferroptosis-Related Marker and Correlates with Immune Microenvironment in Lung Adenocarcinoma

“…The reduction in GAPDH expression was prevented by the ferroptosis inhibitor ferrostatin-1. Additionally, GAPDH knockdown boosted Fe 2+ -induced ferroptosis within tumor cells [ 21 ]. These results imply that ferroptosis affects glycolysis levels in lung cancer cells and that GAPDH may serve as a prognostic sign for lung cancer patients as well as a marker of ferroptosis.…”

“…It is noteworthy that the overexpression of GAPDH, but not of the other glycolytic enzymes studied, promoted tumor cell survival and resistance to chemotherapy in caspase-independent cell death by preserving a small number of intact mitochondria [ 20 ]. Reduced GAPDH expression in tumors slows the glycolytic pathway, interfering with the energy metabolism of the tumor and enhancing the death of tumor cells caused by ferroptosis [ 21 ]. However, further research is still needed to investigate the direct relationship between GAPDH and ferroptosis.…”

What are inorganic nanozymes? Artificial or inorganic enzymes

“…By its very nature, the metalloenzyme is essentially just a type of functionalized nanomaterial with a metal architecture as an active center, stabilized by amino acids or nucleotides due to the natural selection and evolution. Even limited experiments have already demonstrated that nucleotides or amino acids can significantly improve or generate enzyme-like properties in an inorganic nanomaterial based on its architecture, 136,[265][266][267][268][269][270][271][272][273] providing further evidences that enzymes might have emerged from such evolutionary paths or why biocatalysts need further evolution. In other words, active metal sites in tertiary structures were selected first for their catalytic activity.…”

Metal ions and nanometallic materials in antitumor immunity: Function, application, and perspective

“…Triggered by visible blue light instead of UV light, the photoresponsive system generates Fe 2+ and ROS and inhibits GPX4, which leads to apoptosis- and ferroptosis-dependent cancer cell proliferation inhibition [ 111 ]. TAM polarization from the tumor-promoting M2 type to the tumor-killing M1 type is simultaneously activated by PEG-Fns, which concomitantly inhibits tumor growth and prevents pulmonary metastasis in vivo [ 112 ].

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