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<p>Melanoma has a high incidence and mortality, and current therapies are limited. Here, we developed TCPC, an ER-targeted nanomedicine guided by omics analysis. It consists of curcumin-loaded PEG–PCL nanomicelles coated with a Tannic acid–Cu metal–polyphenol network. Guided by clinical transcriptome mining, we identified ER-stress vulnerabilities to inform material design. RNA-seq and imaging confirmed that TCPC preferentially accumulates in melanoma cells and localizes to the ER. TCPC markedly elevates CHOP expression, which triggers ER Ca²⁺ release, mitochondrial dysfunction, ROS accumulation, and apoptosis. Functionally, TCPC significantly suppresses cell viability, migration, and invasion in vitro. In melanoma xenografts, systemic TCPC treatment slows tumor growth, enhances intratumoral CHOP and Cleaved caspase-3, and induces apoptosis without systemic toxicity. Moreover, pharmacogenomic analyses revealed that CHOP upregulation correlates with increased sensitivity to several agents, and molecular docking highlighted Irinotecan and JQ1 as potential synergistic partners with TCPC. Collectively, this work demonstrates that nanomedicine guided by omics can couple organelle-specific delivery with ER-stress amplification to achieve potent antitumor efficacy. Overall, this work establishes an omics-guided materials strategy that integrates organelle-targeted delivery with ER-stress amplification for effective melanoma therapy.</p> Graphical abstract <p></p>

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Engineering endoplasmic reticulum targeted metal–polyphenol curcumin nanomicelles for melanoma therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月30日

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  • Yixun Zhang,
  • Xuehua Wang,
  • Hongli Zhang,
  • Xin Zhou,
  • Huichan He,
  • Fen Zou,
  • Yangjia Zhuo,
  • Zhouda Cai,
  • Qianfeng Xu,
  • Wenjie Xie,
  • Jundong Lin,
  • Muqi Chen,
  • Wenlian Zheng,
  • Jianwei Chen,
  • Jinsheng Liu,
  • Huikang Yang,
  • Weide Zhong,
  • Ronghua Yang

摘要

Melanoma has a high incidence and mortality, and current therapies are limited. Here, we developed TCPC, an ER-targeted nanomedicine guided by omics analysis. It consists of curcumin-loaded PEG–PCL nanomicelles coated with a Tannic acid–Cu metal–polyphenol network. Guided by clinical transcriptome mining, we identified ER-stress vulnerabilities to inform material design. RNA-seq and imaging confirmed that TCPC preferentially accumulates in melanoma cells and localizes to the ER. TCPC markedly elevates CHOP expression, which triggers ER Ca²⁺ release, mitochondrial dysfunction, ROS accumulation, and apoptosis. Functionally, TCPC significantly suppresses cell viability, migration, and invasion in vitro. In melanoma xenografts, systemic TCPC treatment slows tumor growth, enhances intratumoral CHOP and Cleaved caspase-3, and induces apoptosis without systemic toxicity. Moreover, pharmacogenomic analyses revealed that CHOP upregulation correlates with increased sensitivity to several agents, and molecular docking highlighted Irinotecan and JQ1 as potential synergistic partners with TCPC. Collectively, this work demonstrates that nanomedicine guided by omics can couple organelle-specific delivery with ER-stress amplification to achieve potent antitumor efficacy. Overall, this work establishes an omics-guided materials strategy that integrates organelle-targeted delivery with ER-stress amplification for effective melanoma therapy.

Graphical abstract