Polyvalent Aptamer\nNanodrug Conjugates Enable Efficient\nTumor Cuproptosis Therapy Through Copper Overload and Glutathione\nDepletion

Cuproptosis, a recently identified form of copper-dependent\ncell\ndeath, shows promising tumor suppressive effects with minimal drug\nresistance. However, its therapeutic efficacy is hampered by its dependence\non copper ions and the glutathione (GSH)-rich microenvironment in\ntumors. Here, we have developed polyvalent aptamer nanodrug conjugates\n(termed CuPEs@PApt) with a nucleosome-like structure to improve tumor\ncuproptosis therapy by exploiting mitochondrial copper overload and\nGSH depletion. Polyvalent aptamer (PApt), comprising polyvalent epithelial\ncell adhesion molecule aptamers for tumor targeting and repetitive\nPolyT sequences for copper chelation, facilitates efficient loading\nand targeted delivery of copper peroxide-Elesclomol nanodots (CuPEs).\nUpon internalization by tumor cells, Elesclomol released from CuPEs@PApt\naccumulates copper ions in mitochondria to initiate cuproptosis, while\nlysosomal degradation of CuP nanodots generates exogenous Cu<sup>2+</sup> and H<sub>2</sub>O<sub>2</sub>, triggering a Fenton-like reaction\nfor GSH depletion to enhance cuproptosis. In vitro and in vivo experiments\nconfirm the efficacy of this strategy in inducing tumor cell cuproptosis\nand immunogenic cell death, the latter contributing to the activation\nof the antitumor immune response for synergistic tumor growth inhibition.