The copper age in cancer treatment: From copper metabolism to cuproptosis

Enzyme Core Spherical Nucleic Acid That Enables Enhanced Cuproptosis and Antitumor Immune Response through Alleviating Tumor Hypoxia

“…Catalase (CAT), a kind of enzyme widely existing in organism, is capable of efficiently catalyzing the release of O 2 from H 2 O 2 , which is an effective means to relieve tumor hypoxia based on endogenous oxygen supply. − However, inherent shortcomings, such as biological instability, limited target specificity, and challenges in biological delivery, have limited the practical utility of natural catalase. To address these limitations, enzyme immobilization and modification strategies have been explored to reduce the sensitivity of natural enzymes to physical parameters such as temperature and pH, thereby increasing their functional efficiency. − Compared to the low efficiency and high cost of nanomaterial-based enzyme immobilization strategies, DNA offers advantages such as high biological safety, strong affinity, and ease of functionalization. − For instance, the Mirkin group introduced the concept of spherical nucleic acids (SNA) as an effective strategy for DNA-based enzyme modification. − However, ensuring reliable enzyme immobilization and protection requires dense DNA modification, which can potentially compromise enzyme activity or even lead to enzyme inactivation if extensive chemical modifications are made at the active sites. − Therefore, the development of a novel method for low-density chemical grafting that can immobilize and protect enzymes without affecting their activity is of practical importance.…”

Bioactive Layered Double Hydroxides for Synergistic Sonodynamic/Cuproptosis Anticancer Therapy with Elicitation of the Immune Response

“…15−17 The potential mechanism of cuproptosis involves Cu ions directly binding to lipoacylated proteins of the tricarboxylic acid cycle, leading to anomalous oligomerization of lipoacylated proteins and downregulation of Fe−S cluster proteins, which together induce proteotoxic stress responses and eventually lead to cell death. 18,19 However, cuproptosis is hampered by a limited intracellular Cu concentration. Therefore, the development of advanced copper carriers is urgently needed.…”

“…Moreover, SDT monotherapy exhibits limited efficacy in the treatment of aggressive, fast-growing, and metastatic malignancies. Therefore, synergistic antitumor strategies that involve the combination of multiple therapeutic approaches to achieve highly effective cancer therapy are urgently needed. − Recently, it was shown that when the intracellular copper (Cu) concentration exceeds the threshold for maintaining homeostasis, it leads to severe cytotoxicity, revealing a mechanism of cell death called cuproptosis, which is essentially distinct from those extensively studied forms of cell death, including apoptosis, necroptosis, ferroptosis, and pyroptosis. − The potential mechanism of cuproptosis involves Cu ions directly binding to lipoacylated proteins of the tricarboxylic acid cycle, leading to anomalous oligomerization of lipoacylated proteins and downregulation of Fe–S cluster proteins, which together induce proteotoxic stress responses and eventually lead to cell death. , However, cuproptosis is hampered by a limited intracellular Cu concentration. Therefore, the development of advanced copper carriers is urgently needed.…”

Tumor Microenvironment–Activated Nanostructure to Enhance MRI Capability and Nanozyme Activity for Highly Tumor‐Specific Multimodal Theranostics

“…Metal ion-mediated Fenton-like reactions rapidly increase cytotoxic ROS levels and suppress tumor growth. [1][2][3] Ferroptosis is an example of this process and represents a new pathway of nonapoptotic programmed cell death closely associated with cellular Fe accumulation. [4][5][6][7][8] Ferroptosis therapy avoids the limitations of multidrug resistance because it is mediated by a nonapoptotic cell death pathway, eliminating a primary limitation of traditional chemotherapeutics.…”

“…Unlike Fe-based nanomaterials, Cu-based nanoparticles possess greater catalytic activity and stronger responsiveness to the tumor microenvironment (TME), thus it shows great promise for catalytic therapy of tumors. [3,22] However, the morphology and structure of Cu-based nanoparticles are susceptible to sulfhydryl breakage in proteins or other macromolecules, resulting in catalytic inactivation and a significant decrease in antitumor ability. To avoid these limitations, a core-shell structure may protect Cu-based nanoparticles from leakage and inactivation due to stereo-hindrance.…”