Modulation of Dendritic Cell Function via Nanoparticle-Induced Cytosolic Calcium Changes.

Calcium nanoparticles have been investigated for applications, such as drug and gene delivery. Additionally, Ca2+ serves as a crucial second messenger in the activation of immune cells. However, few studies have systematically studied the effects of calcium nanoparticles on the calcium levels and functions within immune cells. In this study, we explore the potential of calcium nanoparticles as a vehicle to deliver calcium into the cytosol of dendritic cells (DCs) and influence their functions. We synthesized calcium hydroxide nanoparticles, coated them with a layer of silica to prevent rapid degradation, and further conjugated them with anti-CD205 antibodies to achieve targeted delivery to DCs. Our results indicate that these nanoparticles can efficiently enter DCs and release calcium ions in a controlled manner. This elevation in cytosolic calcium activates both the NFAT and NF-κB pathways, in turn promoting the expression of costimulatory molecules, antigen-presenting molecules, and pro-inflammatory cytokines. In mouse tumor models, the calcium nanoparticles enhanced the antitumor immune response and augmented the efficacy of both radiotherapy and chemotherapy without introducing additional toxicity. Our study introduces a safe nanoparticle immunomodulator with potential widespread applications in cancer therapy.

Ultra-small platinum nanoparticles on gold nanorods induced intracellular ROS fluctuation to drive megakaryocytic differentiation of leukemia cells.

Chronic myeloid leukemia (CML) is a kind of hematological malignancy featured with retarded differentiation that is highly linked to the level of intracellular reactive oxygen species (ROS). In this work, ultra-small platinum nanoparticles deposited on gold nanorods (Au@Pt) were synthesized and applied on the CML cells. It was shown that Au@Pt had multienzyme-like activities that induced a fluctuation of the intracellular ROS level over the incubation time, depending on their temporal locations in the cells. The ROS fluctuation triggered cellular autophagy and enhanced the level of autophagic protein Beclin-1, which caused the degradation of fusion protein BCR-ABL, the key factor of retarded differentiation and led to the downregulation of phosphorylation of PI3K and AKT. These interactions together broke retarded differentiation and drove the CML cells to differentiate towards megakaryocytes, which is of great significance in enhancing leukemic cell apoptosis. Therefore, Au@Pt exhibited a novel function and promising therapeutic potential for the CML treatment.

Co-delivery of homoharringtonine and doxorubicin boosts therapeutic efficacy of refractory acute myeloid leukemia.

Refractory acute myeloid leukemia (AML) remains a challenging hematological malignancy to treat, due to the development of drug resistance, severe complications, and relapse in chemotherapies. Free-drugs combination has demonstrated enhanced therapeutic efficacy in AML, while it requires complicated administration regimens and brings added toxicity. To tackle this complex disease, in this work two clinically applied therapeutics, doxorubicin and homoharringtonine, were assembled into one polymeric micelle to form a co-delivery system (DHM) to facilitate a novel and simple administration regimen. The DHM was systematically investigated in the drug-resistant AML cell line HL60/A as well as in the AML1-ETO+-c-kit+ mouse featuring as a refractory and relapsed AML model following comprehensive characterizations. Compared with the free-drugs combination, DHM significantly enhanced the cellular uptake of the therapeutics, inhibited the cell division and induced a higher rate of cells apoptosis in vitro. More importantly, the intraperitoneal injection of DHM remarkably eradicated leukemia cells in the peripheral blood, bone marrow, spleen and liver of the AML mice and significantly prolonged the survival of the mice without additional systematic toxicity compared with that of the free-drugs combination. In conclusion, the DHM boosted the therapeutic effect of clinically applied chemodrugs as well as provided a novel platform for multi-drugs co-delivery against refractory and relapsed AML, therefore holding promising potential for translational medicine.

Stiffness of cationized gelatin nanoparticles is a key factor determining RNAi efficiency in myeloid leukemia cells.

Here we demonstrated that the stiffness of cationized gelatin nanoparticles determined the efficiency of RNAi in myeloid leukemia cells when the particle size and surface charges were kept constant. The siRNA delivery system with an elastic modulus of 0.87 MPa showed the largest siRNA uptake and RNAi efficiency for hard-to-transfect suspension cells.