Cu2+-Anchored Carbon Nano-Photocatalysts for Visible Water Splitting to Boost Hydrogen Cuproptosis

Both hydrogen (H₂) and copper ions (Cu⁺) can be used as anti-cancer treatments. However, the continuous generation of H₂ molecules and Cu⁺ in specific sites of tumors is challenging. Here we anchored Cu²⁺ on carbon photocatalyst (Cu@CDCN) to allow the continuous generation of H₂ and hydrogen peroxide (H₂O₂) in tumors using the two-electron process of visible water splitting. The photocatalytic process also generated redox-active Cu-carbon centers. Meanwhile, the Cu²⁺ residues reacted with H₂O₂ (the obstacle to the photocatalytic process) to accelerate the two-electron process of water splitting and cuprous ion (Cu⁺) generation, in which the Cu²⁺ residue promoted a pro-oxidant effect with glutathione through metal-reducing actions. Both H₂ and Cu⁺ induced mitochondrial dysfunction and intracellular redox homeostasis destruction, which enabled hydrogen therapy and cuproptosis to inhibit cancer cell growth and suppress tumor growth. Our research is the first attempt to integrate hydrogen therapy and cuproptosis using metal-enhanced visible solar water splitting in nanomedicine, which may provide a safe and effective cancer treatment.     

Photothermally Triggered Copper Payload Release for Cuproptosis-Promoted Cancer Synergistic Therapy

Cuproptosis is a new form of programmed cell death and exhibits enormous potential in cancer treatment. However, reducing the undesirable Cu ion release in normal tissue and maximizing the copper-induced therapeutic effect in cancer sites are two main challenges. In this study, we constructed a photothermally triggered nanoplatform (Au@MSN-Cu/PEG/DSF) to realize on-demand delivery for synergistic therapy. The released disulfiram (DSF) chelated with Cu²⁺ in situ to generate highly cytotoxic bis(diethyldithiocarbamate)copper (CuET), causing cell apoptosis, and the formed Cu⁺ species promoted toxic mitochondrial protein aggregation, leading to cell cuproptosis. Synergistic with photothermal therapy, Au@MSN-Cu/PEG/DSF could effectively kill tumor cells and inhibit tumor growth (inhibition rate up to 80.1 %). These results provide a promising perspective for potential cancer treatment based on cuproptosis, and may also inspire the design of advanced nano-therapeutic platforms.     

Metalloallostery and Transition Metal Signaling: Bioinorganic Copper Chemistry Beyond Active Sites

Transition metal chemistry is essential to life, where metal binding to DNA, RNA, and proteins underpins all facets of the central dogma of biology. In this context, metals in proteins are typically studied as static active site cofactors. However, the emergence of transition metal signaling, where mobile metal pools can transiently bind to biological targets beyond active sites, is expanding this conventional view of bioinorganic chemistry. This Minireview focuses on the concept of metalloallostery, using copper as a canonical example of how metals can regulate protein function by binding to remote allosteric sites (e.g., exosites). We summarize advances in and prospects for the field, including imaging dynamic transition metal signaling pools, allosteric inhibition or activation of protein targets by metal binding, and metal-dependent signaling pathways that underlie nutrient vulnerabilities in diseases spanning obesity, fatty liver disease, cancer, and neurodegeneration.