Rationale: Ferroptosis drugs inducing cancer immunogenic cell death (ICD) have shown the potential of immunotherapy in vivo . However, the current ferroptosis drugs usually induce the insufficient immune response because of the low ROS generation efficiency. Methods: Herein, we design zinc-fluorouracil metallodrug networks (Zn-Fu MNs), by coordinating Zn and Fu via facile one-pot preparation, to inactivate mitochondrial electron transport for enhanced ROS production and immune activation. Results: Zn-Fu MNs can be responsive toward acidity and adenosine triphosphate (ATP) with the release of Fu and Zn 2+ , during which Zn 2+ can induce mitochondrion disruption to produce ROS, resulting in ferroptosis of cancer cells and 5-Fu interferes with DNA synthesis in nuclei with 19 F-MRI signal to be switched on for correlating drug release. With the synergistic effect of DNA damage and ferroptosis, the cancer cells are forced to promote ICD. Thereby, Zn-Fu MNs exhibit the excellent immune response without any other antigens loading. As a result, the infiltration of T cells within tumor and activation of immune cells in spleen have been greatly enhanced. Conclusions: Combined DNA damage and ferroptosis, Zn-Fu MNs induce the violent emission of tumor associated antigens within cancer cells which will sensitize naive dendritic cells and promote the activation and recruitment of cytotoxic T lymphocytes to exterminate cancer cells. Therefore, the obtained Zn-Fu MNs as ferroptosis inducers can effectively remodel immunosuppressive tumor microenvironment and activate antitumor immune reaction.
The targeting of tumor metabolism as a novel strategy for cancer therapy has attracted tremendous attention. Herein, we develop a dual metabolism inhibitor, Zn–carnosine metallodrug network nanoparticles (Zn-Car MNs), which exhibits good Cu-depletion and Cu-responsive drug release, causing potent inhibition of both OXPHOS and glycolysis. Notably, Zn-Car MNs can decrease the activity of cytochrome c oxidase and the content of NAD+, so as to reduce ATP production in cancer cells. Thereby, energy deprivation, together with the depolarized mitochondrial membrane potential and increased oxidative stress, results in apoptosis of cancer cells. In result, Zn-Car MNs exerted more efficient metabolism-targeted therapy than the classic copper chelator, tetrathiomolybdate (TM), in both breast cancer (sensitive to copper depletion) and colon cancer (less sensitive to copper depletion) models. The efficacy and therapy of Zn-Car MNs suggest the possibility to overcome the drug resistance caused by metabolic reprogramming in tumors and has potential clinical relevance.
Hepatic ischemia–reperfusion (I/R) injury accompanied by oxidative stress is responsible for postoperative liver dysfunction and failure of liver surgery. However, the dynamic non-invasive mapping of redox homeostasis in deep-seated liver during hepatic I/R injury remains a great challenge. Herein, inspired by the intrinsic reversibility of disulfide bond in proteins, a kind of reversible redox-responsive magnetic nanoparticles (RRMNs) is designed for reversible imaging of both oxidant and antioxidant levels (ONOO–/GSH), based on sulfhydryl coupling/cleaving reaction. We develop a facile strategy to prepare such reversible MRI nanoprobe via one-step surface modification. Owing to the significant change in size during the reversible response, the imaging sensitivity of RRMNs is greatly improved, which enables RRMNs to monitor the tiny change of oxidative stress in liver injury. Notably, such reversible MRI nanoprobe can non-invasively visualize the deep-seated liver tissue slice by slice in living mice. Moreover, this MRI nanoprobe can not only report molecular information about the degree of liver injury but also provide anatomical information about where the pathology occurred. The reversible MRI probe is promising for accurately and facilely monitoring I/R process, accessing injury degree and developing powerful strategy for precise treatment.
Ferroptosis, as a type of programmed cell death process, enables effective damage to various cancer cells. However, we discovered that persistent oxidative stress during ferroptosis can upregulate the apurinic/apyrimidinic endonuclease 1 (APE1) protein that induces therapeutic resistance (“ferroptosis resistance”), resulting in an unsatisfactory treatment outcome. To address APE1-induced therapeutic resistance, we developed a GSH/APE1 cascade activated therapeutic nanoplatform (GAN). Specifically, the GAN is self-assembled by DNA-functionalized ultrasmall iron oxide nanoparticles and further loaded with drug molecules (drug-GAN). GSH-triggered GAN disassembly can “turn on” the catalysis of GAN to induce efficient lipid peroxidation (LPO) for ferroptosis toward the tumor, which could upregulate APE1 expression. Subsequently, upregulated APE1 can further trigger accurate drug release for overcoming ferroptosis resistance and inducing the recovery of near-infrared fluorescence for imaging the dynamics of APE1. Importantly, adaptive drug release can overcome the adverse effects of APE1 upregulation by boosting intracellular ROS yield and increasing DNA damage, to offset APE1’s functions of antioxidant and DNA repair, thus leading to adaptive ferroptosis. Moreover, with overexpressed GSH and upregulated APE1 in the tumor as stimuli, the therapeutic specificity of ferroptosis toward the tumor is greatly improved, which minimized nonspecific activation of catalysis and excessive drug release in normal tissues. Furthermore, a switchable MRI contrast from negative to positive is in sync with ferroptosis activation, which is beneficial for monitoring the ferroptosis process. Therefore, this adapted imaging and therapeutic nanoplatform can not only deliver GSH/APE1-activated lipid peroxide mediated adaptive synergistic therapy but also provided a switchable MRI/dual-channel fluorescence signal for monitoring ferroptosis activation, drug release, and therapy resistance dynamics in vivo, leading to high-specificity and high-efficiency adaptive ferroptosis therapy.
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