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Oxidative stress and deficient bioenergetics are key players in the pathological process of cerebral ischemia reperfusion injury (I/R). As a mitochondrial iron storage protein, mitochondrial ferritin (FtMt) plays a pivotal role in protecting neuronal cells from oxidative damage under stress conditions. However, the effects of FtMt in mitochondrial function and activation of apoptosis under cerebral I/R are barely understood. In the present study, we found that FtMt deficiency exacerbates neuronal apoptosis via classical mitochondria-depedent pathway and the endoplasmic reticulum (ER) stress pathway in brains exposed to I/R. Conversely, FtMt overexpression significantly inhibited oxygen and glucose deprivation and reperfusion (OGD/R)-induced apoptosis and the activation of ER stress response. Meanwhile, FtMt overexpression rescued OGD/R-induced mitochondrial iron overload, mitochondrial dysfunction, the generation of reactive oxygen species (ROS) and increased neuronal GSH content. Using the Seahorse and O2K cellular respiration analyser, we demonstrated that FtMt remarkably improved the ATP content and the spare respiratory capacity under I/R conditions. Importantly, we found that glucose consumption was augmented in FtMt overexpressing cells after OGD/R insult; overexpression of FtMt facilitated the activation of glucose 6-phosphate dehydrogenase and the production of NADPH in cells after OGD/R, indicating that the pentose-phosphate pathway is enhanced in FtMt overexpressing cells, thus strengthening the antioxidant capacity of neuronal cells. In summary, our results reveal that FtMt protects against I/R-induced apoptosis through enhancing mitochondrial bioenergetics and regulating glucose metabolism via the pentose-phosphate pathway, thus preventing ROS overproduction, and preserving energy metabolism.

Recurrence and drug resistance of acute myeloid leukemia (AML) remained the leading causes of death in blood cancers. The interaction of chemokine receptor 4/chemokine ligand 12 (CXCR4/CXCL12) leads to the trace residue of AML cells in patients after traditional chemotherapy, which hidden security danger for subsequent recurrence. The toxic and side effects of conventional chemotherapy on normal tissues also severely limited the clinical therapeutic efficacy of AML. To overcome these problems, a multifunctional nanoplatform of Fe3O4@Pt composite nanozyme conjugating CXCR4 antagonist was designed, aiming to synergistically treat AML for the first time, in which, the CXCR4 antagonist was used to specifically target AML cells as well as to significantly interfere CXCR4/CXCL12 axis. In the mildly acidic lysosome microenvironment, highly toxic reactive oxygen species (ROS) was generated through the sequential catalytic reactions of Fe3O4@Pt to trigger AML cells apoptosis, leaving the normal cells unharmed. This nanoplatform exhibited a superior synergistic therapeutic efficacy against AML in vitro and in vivo, preventing AML cells from homing to bone marrow and migrating to spleen, lung and liver, which in turn prolonged the survival period of AML mice. Therefore, this designed nanoplatform holds potentials for clinic applications in AML treatment.

Chemotherapy has been major and standard strategy that is widely used in the treatment of acute myeloid leukemia (AML). However, for the lack of specificity of free drugs, patients are suffering from the non-specific toxicity and high recurrence rate. The C-X-C chemokine receptor type 4 (CXCR4) and cluster determinant 44 (CD44) are becoming highly appealing target candidates as the markers for AML relapse. Here, we designed and fabricated pH-responsive CXCR4 and CD44 dual-targeted nanosystems, based on Prussian blue nanoparticles (PBNPs) for AML therapy. The polyethylene glycol-grafted polyethylenimine with benzoic-imine bond modified PBNPs were synthesized and then functionalized with CXCR4 targeting peptide E5 and CD44 targeting moiety hyaluronic acid (HA). Daunorubicin (DNR) was selected as a model anti-AML drug. The dual-targeted PBNPs achieved not only effective endosomal escape but also prolonged blood retention time in physiological condition. Moreover, the cleavage of PEG chain in the endosome enabled to rapidly release DNR. The dual-targeted PBNPs exhibited increased internalization, improved anti-HL60 cells effect, and reduced HL60 cells migration and adhesion induced by bone marrow stroma cells compared with mono-targeted PBNPs. The in vivo results showed that DNR-loaded dual-targeted PBNPs displayed more powerful capability to block the proliferation of leukemia blasts in bone marrow, peripheral blood and spleen in AML mice xenograft model. More importantly, the dual-targeted PBNPs also inhibited leukemia blasts metastatic to liver and spleen, reversed splenomegaly, and extended the overall survival. Therefore, the dual-targeted PBNPs represent a promising strategy for advancing therapeutics for AML therapy.