Triphenylphosphine-Chitosan Functionalized MoS2 Nanosheets Delivering Elesclomol-Cu(II) Complex for Enhanced Cuproptosis-Mediated Cancer Therapy

  • Biomacromolecules. 2025 Aug 11;26(8):5438-5449. doi: 10.1021/acs.biomac.5c01024.
Shaohui Xu  1  2 ,  Ze Chen  3 ,  Yifei Huang  2 ,  Yinan Zhong  2 ,  Wei Chen  2
Affiliations
  • 1. Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
  • 2. Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
  • 3. College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China.
PMID: 40740006 DOI: 10.1021/acs.biomac.5c01024
Abstract

Cuproptosis, a newly identified form of the copper-induced cell death pathway, offers therapeutic potential for Cancer therapy but is limited by poor mitochondrial targeting and systemic toxicity. We developed a mitochondria-targeted nanoplatform (EsCu@TCM) by loading elesclomol-Cu(II) (EsCu) onto triphenylphosphine-chitosan-modified MoS2 nanosheets. EsCu@TCM enables NIR-triggered release, efficient photothermal conversion, and precise mitochondrial delivery. In vitro, EsCu@TCM promoted mitochondrial copper accumulation, disrupted membrane potential, and depleted ATP (to 21.9% of the control), inducing ∼3-fold Apoptosis enhancement versus free EsCu. Cuproptosis markers, including FDX1 downregulation and DLAT oligomerization, were confirmed. Under NIR irradiation, EsCu@TCM suppressed ATP7A expression, enhancing intracellular copper retention. In vivo, EsCu@TCM+L showed effective tumor accumulation, tumor inhibition (volume reduction to 21.0%), minimal systemic toxicity, and strong Cuproptosis activation. This work presents a synergistic strategy combining photothermal therapy and Cuproptosis for targeted Cancer treatment.

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