Lipid peroxides accumulation induced ferroptosis is an effective cell death pathway for cancer therapy. However, the hypoxic condition of tumor microenvironment significantly suppresses the efficacy of ferroptosis. Here, we design a novel nanoplatform to overcome hypoxia-induced ferroptosis resistance. Specifically, we synthesize a novel kind of perfluorocarbon (PFOB)@manganese oxide (MnOx) core-shell nanoparticles (PM-CS NPs). Owing to the good carrier of O 2 as fuel, PM-CS NPs can induce higher level of ROS generation, lipid peroxidation and GSH depletion, as well as lower activity of GPX4, compared with MnOx NPs alone. Moreover, the supplement of O 2 can relieve tumor hypoxia to break down the storage of intracellular lipid droplets and increase expression of ACSL4 (a symbol for ferroptosis sensitivity). Furthermore, upon stimulus of GSH or acidity, PM-CS NPs exhibit the "turn on" 19 F-MRI signal and activatable T 1 /T 2 -MRI contrast for correlating with the release of Mn. Finally, PM-CS NPs exert high cancer inhibition rate for ferroptosis based therapy via synergetic combination of O 2 -mediated enhancement of key pathways of ferroptosis.
Ferroptosis exhibits potential to damage drugresistant cancer cells. However, it is still restricted with the "off-target" toxicity from the undesirable leakage of metal ions from ferroptosis agents, and the lack of reliable imaging for monitoring the ferroptosis process in living systems. Herein, we develop a novel ternary alloy PtWMn nanocube as a Mn reservoir, and further design a microenvironment-triggered nanoplatform that can accurately release Mn ions within the tumor to increase reactive oxygen species (ROS) generation, produce O 2 and consume excess glutathione for synergistically enhancing nonferrous ferroptosis. Moreover, this nanoplatform exerts a responsive signal in high-field magnetic resonance imaging (MRI), which enables the real-time report of Mn release and the monitoring of ferroptosis initiation through the signal changes of T 1 -/ T 2 -MRI. Thus, our nanoplatform provides a novel strategy to store, deliver and precisely release Mn ions for MRI-guided high-specificity ferroptosis therapy.
Combination therapy via stimulus-responsive drug release is known to improve treatment efficacy and minimize side effects. However, the use of low-abundance cancer biomarkers as molecular triggers to induce efficient drug release for combination therapy still remains a challenge. Herein, we developed a dual microRNA-responsive drug nanocarrier for catalytic release of doxorubicin (Dox) and small interfering RNA (siRNA) in cancerous cells for combined chemotherapy and gene therapy with logic operation. The nanocarrier is constructed by assembling two duplexes of DNA/RNA and Dox molecules onto DNA-functionalized gold nanoparticles. Two microRNA molecules (miRNA-21 and miRNA-10b overexpressed in MDA-MB-231) could alternatively catalyze the disassembly of the nanocarrier through a thermodynamically driven entropy gain process, during which Dox molecules are released, and the two pairs of released DNA/RNA duplex hybridize to generate siRNA (siBcl-2) in situ by strand displacement reactions. Quantum dots are used to track the process in living cells. The AND logic gate-based drug release system allows effective treatment of specific cancer cell types according to miRNA expression patterns. This strategy represents an effective means to overcome multidrug resistance and improve therapeutic effects.
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.
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