Synchronized ros burst and proteotoxicity in tumors: spatiotemporally guided cu-mof activates fenton-cuproptosis-dna damage cascade for tumor therapy

Copper ions (Cu²⁺) trigger cuproptosis to suppress tumors, but glutathione (GSH) chelation and hypoxic suppression of lipoylated proteins in the tumor microenvironment (TME) limit efficacy. In this study, we design a pH-responsive copper-based metal-organic framework (Cu-MOF) loaded with a manganese complex (MnPC) to to synchronize reactive oxygen species (ROS) burst and proteotoxicity, triggering a Fenton-cuproptosis-DNA damage cascade for enhanced tumor therapy. In acidic TME, Cu-MOF releases Cu²⁺ ions, initiating a Fenton reaction that generates hydroxyl radicals for ROS-mediated damage. Concurrently, the released Cu²⁺ ions, after reduction by GSH to Cu⁺, accumulate in the mitochondrial matrix, inhibiting the tricarboxylic acid cycle. This leads to the aggregation of lipoylated proteins, a hallmark of cuproptosis, which induces strong proteotoxicity and amplifies cell death signals. Furthermore, the MnPC cause direct DNA double-strand breaks, creating a third layer of damage that reinforces tumor cell apoptosis. This multifaceted approach not only targets tumor cells directly but also modulates the tumor microenvironment, creating a synergistic effect that enhances overall treatment outcomes. This study provides a new perspective on the integration of ROS-based therapies with proteotoxicity induction, offering a promising avenue for the development of more effective and targeted cancer treatments.