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

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.