All-Trans-Retinoic Acid-Adjuvanted mRNA Vaccine Induces Mucosal Anti-Tumor Immune Responses for Treating Colorectal Cancer.

Messenger RNA (mRNA) cancer vaccines are a new class of immunotherapies that can activate the immune system to recognize and destroy cancer cells. However, their effectiveness in treating colorectal cancer located on the mucosal surface of the gut is limited due to the insufficient activation of mucosal immune response and inadequate infiltration of cytotoxic T cells into tumors. To address this issue, a new mRNA cancer vaccine is developed that can stimulate mucosal immune responses in the gut by co-delivering all-trans-retinoic acid (ATRA) and mRNA using lipid nanoparticle (LNP). The incorporation of ATRA has not only improved the mRNA transfection efficiency of LNP but also induced high expression of gut-homing receptors on vaccine-activated T cells. Additionally, the use of LNP improves the aqueous solubility of ATRA, eliminating the need for toxic solvents to administer ATRA. Upon intramuscular injections, ATRA-adjuvanted mRNA-LNP significantly increase the infiltration of antigen-specific, cytotoxic T cells in the lamina propria of the intestine, mesenteric lymph nodes, and orthotopic colorectal tumors, resulting in significantly improved tumor inhibition and prolonged animal survival compared to conventional mRNA-LNP without ATRA. Overall, this study provides a promising approach for improving the therapeutic efficacy of mRNA cancer vaccines against colorectal cancer.

Two-Pronged Intracellular Co-Delivery of Antigen and Adjuvant for Synergistic Cancer Immunotherapy.

Nanovaccines have emerged as promising alternatives or complements to conventional cancer treatments. Despite the progresses, specific co-delivery of antigen and adjuvant to their corresponding intracellular destinations for maximizing the activation of antitumor immune responses remains a challenge. Herein, a lipid-coated iron oxide nanoparticle is delivered as nanovaccine (IONP-C/O@LP) that can co-deliver peptide antigen and adjuvant (CpG DNA) into cytosol and lysosomes of dendritic cells (DCs) through both membrane fusion and endosome-mediated endocytosis. Such two-pronged cellular uptake pattern enables IONP-C/O@LP to synergistically activate immature DCs. Iron oxide nanoparticle also exhibits adjuvant effects by generating intracellular reactive oxygen species, which further promotes DC maturation. IONP-C/O@LP accumulated in the DCs of draining lymph nodes effectively increases the antigen-specific T cells in both tumor and spleen, inhibits tumor growth, and improves animal survival. Moreover, it is demonstrated that this nanovaccine is a general platform of delivering clinically relevant peptide antigens derived from human papilloma virus 16 to trigger antigen-specific immune responses in vivo.

Nanotechnology-enhanced immunotherapy for metastatic cancer.

A vast majority of cancer deaths occur as a result of metastasis. Unfortunately, effective treatments for metastases are currently lacking due to the difficulty of selectively targeting these small, delocalized tumors distributed across a variety of organs. However, nanotechnology holds tremendous promise for improving immunotherapeutic outcomes in patients with metastatic cancer. In contrast to conventional cancer immunotherapies, rationally designed nanomaterials can trigger specific tumoricidal effects, thereby improving immune cell access to major sites of metastasis such as bone, lungs, and lymph nodes, optimizing antigen presentation, and inducing a persistent immune response. This paper reviews the cutting-edge trends in nano-immunoengineering for metastatic cancers with an emphasis on different nano-immunotherapeutic strategies. Specifically, it discusses directly reversing the immunological status of the primary tumor, harnessing the potential of peripheral immune cells, preventing the formation of a pre-metastatic niche, and inhibiting the tumor recurrence through postoperative immunotherapy. Finally, we describe the challenges facing the integration of nanoscale immunomodulators and provide a forward-looking perspective on the innovative nanotechnology-based tools that may ultimately prove effective at eradicating metastatic diseases.

Continuous response fluorescence sensor for three small molecules based on nitrogen-doped carbon quantum dots from prunus lannesiana and their logic gate operation.

In this study, an environmentally friendly and water-soluble nitrogen-doped carbon quantum dots (N-CQDs) with quantum yield (QY) of 8.59% were prepared by one-step hydrothermal synthesis without any chemical reagent using the leaves of prunus lannesiana as precursors. The properties and quality of N-CQDs were investigated by Ultraviolet-visible absorption spectroscopy, infrared spectroscopy, X-ray photoelectron spectroscopy, zeta potential, high-resolution transmission electron microscopy and fluorescence spectroscopy. The fluorescence of the prepared N-CQDs can be quenched by Fe3+ through the synergistic effect of the formation of non-fluorescent complex and internal filtration effect (IFE) between Fe3+ and N-CQDs. And the quenched fluorescence can be "turned on" after adding ascorbic acid (AA) because Fe3+ can be released from the surface of N-CQDs through the redox reaction between AA and Fe3+. While the restored fluorescence can be "turned off" again by hydrogen peroxide (H2O2) due to the re-oxidation of Fe2+ to Fe3+. So, the three inputs "logic gate" is achieved and the "on-off-on-off" continuous response fluorescence sensor is formed, which can be applied for the continuous detection of Fe3+, AA and H2O2 with the linear range of 40-260 µM, 10-200 µM and 40-140 µM, respectively. Finally, the sensor was successfully applied to determine Fe3+, AA and H2O2 in real samples with the satisfactory recoveries (95.35%-104.10%) and repeatability (relative standard deviation (RSD) ≤ 1.68%). The continuous response fluorescence sensor prepared by simple green synthesis route has the characteristics of fast response, acceptable sensitivity and good selectivity.

Quantitative Mapping of Glutathione within Intracranial Tumors through Interlocked MRI Signals of a Responsive Nanoprobe.

Studies reveal that malignant tumors feature uneven distributions of some key biomarkers across the entire tumorous region. Nevertheless, only very limited progress has been made towards non-invasive and quantitative detection of tumor-specific biomarkers in vivo, especially with clinically compatible imaging modalities. Reported here is an Fe3 O4 nanoparticle-based glutathione (GSH) responsive magnetic resonance imaging (MRI) probe that can form particle aggregates within tumors in vivo to give rise to strong GSH concentration dependent interlocked relaxivities. A quantitative correlation between the interlocked MRI signals and local GSH concentration was established, and further applied for mapping the heterogeneous distribution of GSH within an intracranial tumor (2.4 mm × 1.6 mm) in vivo. This methodology will offer a practical route for quantitatively mapping tumor-specific biomarkers in vivo with unlimited detection depth, which largely challenges optical-imaging-based approaches.

pH-Sensitive Ratiometric Fluorescent Probe for Evaluation of Tumor Treatments.

Determining therapeutic efficacy is critical for tumor precision theranostics. In order to monitor the efficacy of anti-cancer drugs (e.g., Paclitaxel), a pH-sensitive ratiometric fluorescent imaging probe was constructed. The pH-sensitive ratiometric fluorescent dye ANNA was covalently coupled to the N-terminal of the cell-penetrating TAT peptide through an amidation reaction (TAT-ANNA). The in vitro cellular experiments determined that the TAT-ANNA probe could penetrate the cell membrane and image the intracellular pH in real time. The in vivo experiments were then carried out, and the ratiometric pH response to the state of the tumor was recorded immediately after medication. The TAT-ANNA probe was successfully used to monitor the pharmacodynamics of anti-cancer drugs in vivo.

Recent advancements in biocompatible inorganic nanoparticles towards biomedical applications.

Due to their intrinsic physical properties potentially useful for imaging and therapy as well as their highly engineerable surface, biocompatible inorganic nanoparticles offer novel platforms to develop advanced diagnostic and therapeutic agents for improved detection and more efficacious treatment of major diseases. The in vivo application of inorganic nanoparticles was demonstrated more than two decades ago, however it turns out to be very complicated as nanomaterials exhibit much more sophisticated pharmacokinetic properties than conventional drugs. In this review, we first discuss the in vivo behavior of inorganic nanoparticles after systematic administration, including the basic requirements for nanoparticles to be used in vivo, the impact of the particles' physicochemical properties on their pharmacokinetics, and the effects of the protein corona formed across the nano-bio interface. Next, we summarize the state-of-the-art of the preparation of biocompatible inorganic nanoparticles and bioconjugation strategies for obtaining target-specific nanoprobes. Then, the advancements in sensitive tumor imaging towards diagnosis and visualization of the abnormal signatures in the tumor microenvironment, together with recent studies on atherosclerosis imaging are highlighted. Finally, the future challenges and the potential for inorganic nanoparticles to be translated into clinical applications are discussed.

Electrocatalytic Behavior of Hemoglobin Oxidation of Hydrazine Based on ZnO Nano-rods with Carbon Nanofiber Modified Electrode.

A novel biosensor was developed by immobilizing hemoglobin (Hb) on a glassy carbon electrode (GCE) modified with a composite of ZnO nano-rods and carbon nanofiber (CNF), a strong reducer, hydrazine, was firstly used to evaluate the electrochemical behavior of Hb on Hb/ZnO/CNF/GCE. UV-vis and circular dichroism (CD) spectra indicated the conformational structure of Hb interaction with ZnO/CNF was predominantly an α-helical structure. The modified electrodes were characterized by scanning electron microscopy (SEM), electron impedance spectroscopy (EIS), and cyclic voltammetry. Electrocatalytic mechanism of Hb to oxidation reaction of hydrazine was suggested. The bioelectrocatalytic activity, kinetic parameters of Michaelis-Menten constant (Km), stability and reproducibility were also investigated. A linear dependence of peak currents to the concentrations of hydrazine was observed in the range from 1.98 × 10(-5) to 1.71 × 10(-3) mol L(-1) with a correlation coefficient of 0.998, and a detection limit (S/N = 3) of 6.60 µmol L(-1) was estimated.