A CRISPR-Customizable Copper-Coordinated DNA Nanoplatform Potentiates Cuproptosis Through Circadian and Metabolic Pathway Manipulation

Oct 10, 2025ACS nano

A DNA-based copper delivery system enhances copper-triggered cell death by altering daily rhythms and metabolism

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Abstract

A CRISPR-customized copper-DNA nanoplatform (Cu-RNP) may enhance the efficacy of cuproptosis in cancer therapy by manipulating circadian and metabolic pathways.

Cu-RNP induces multimodal cell death, including enhanced cuproptosis, through the disruption of circadian rhythms.
Silencing the BMAL1 gene is associated with downregulation of certain pathways and upregulation of others, leading to increased apoptosis.
The release of copper from Cu-RNP generates cytotoxic hydroxyl radicals, contributing to chemodynamic therapy.
Cu-RNP depletes glutathione (GSH), promoting copper accumulation in mitochondria, which is linked to cuproptosis.
In vitro and in vivo results indicate that Cu-RNP sensitizes cancer cells to cuproptosis, leading to a significant antitumor response.

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Despite the promise of cuproptosis in antitumor therapy, developing strategies to enhance its therapeutic efficacy within the tumor microenvironment remains a challenge. Inspired by the chronotherapy that manipulate circadian rhythms to enhance drug effectiveness, herein we report for a CRISPR-customized copper-DNA nanoplatform (Cu-RNP) that synergistically induces multimodal cell death, including potentiated cuproptosis, by manipulating circadian and metabolic pathways. Cu-RNP integrates coordination-driven self-assembly of Cu-DNA nanospheres with Cas13d/crRNA ribonucleoproteins targeting BMAL1. Upon cellular internalization, the acidic and reducing endo/lysosomal environment triggers Cu-RNP disassembly, releasing RNP to silence BMAL1 and disrupt circadian oscillations, leading to1 downregulation and21 upregulation, thereby inducing apoptosis. Simultaneously, liberated Cugenerates cytotoxic hydroxyl radicals for chemodynamic therapy (CDT) and concurrently depletes GSH, promoting mitochondrial copper overload for cuproptosis. Importantly, we demonstrate that silencing BMAL1 disrupts circadian rhythms, inhibits glycolysis, enhances mitochondrial respiration, and redirects metabolic flux to the TCA cycle, thereby amplifying the cell's vulnerability to copper-induced cuproptosis. In vitro and in vivo results demonstrate that Cu-RNP sensitizes cancer cells to cuproptosis and elicit strong antitumor response through the synergistic combination of cuproptosis, CDT, apoptosis, and circadian-metabolic modulation. This study demonstrates a mechanistic link between BMAL1-regulated circadian rhythms and cuproptosis sensitivity, suggesting a potential treatment strategy for multimodal, cuproptosis-potentiating cancer therapies. 2+ 2+ WEE p

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A CRISPR-Customizable Copper-Coordinated DNA Nanoplatform Potentiates Cuproptosis Through Circadian and Metabolic Pathway Manipulation

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