In the 10 years that have passed since the Nobel prize-winning discovery of RNA interference (RNAi), billions of dollars have been invested in the therapeutic application of gene silencing in humans. Today, there are promising data from ongoing clinical trials for the treatment of age-related macular degeneration and respiratory syncytial virus. Despite these early successes, however, the widespread use of RNAi therapeutics for disease prevention and treatment requires the development of clinically suitable, safe and effective drug delivery vehicles. Here, we provide an update on the progress of RNAi therapeutics and highlight novel synthetic materials for the encapsulation and intracellular delivery of nucleic acids.

Knocking down barriers: advances in siRNA delivery

https://www.cell.com/cell/pdf/S0092-8674(09)00446-2.pdf

Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

Activation of hepatic stellate cells (HSCs) in liver injury is the primary driver of hepatic fibrosis. In this Review, Tsuchida and Friedman detail the varied intracellular and extracellular signalling pathways leading to HSC activation, as well as the role of HSCs in liver fibrosis resolution and as therapeutic targets. Hepatic fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix resulting from chronic liver injury of any aetiology, including viral infection, alcoholic liver disease and NASH. Activation of hepatic stellate cells (HSCs) — transdifferentiation of quiescent, vitamin-A-storing cells into proliferative, fibrogenic myofibroblasts — is now well established as a central driver of fibrosis in experimental and human liver injury. Yet, the continued discovery of novel pathways and mediators, including autophagy, endoplasmic reticulum stress, oxidative stress, retinol and cholesterol metabolism, epigenetics and receptor-mediated signals, reveals the complexity of HSC activation. Extracellular signals from resident and inflammatory cells including macrophages, hepatocytes, liver sinusoidal endothelial cells, natural killer cells, natural killer T cells, platelets and B cells further modulate HSC activation. Finally, pathways of HSC clearance have been greatly clarified, and include apoptosis, senescence and reversion to an inactivated state. Collectively, these findings reinforce the remarkable complexity and plasticity of HSC activation, and underscore the value of clarifying its regulation in hopes of advancing the development of novel diagnostics and therapies for liver disease.

Mechanisms of hepatic stellate cell activation

The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an increased risk of cardiovascular disease and diabetes. The metabolic syndrome can be d...

Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation

Immunotherapy has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing, with numerous treatments in clinical and preclinical development. However, a key challenge in the broad implementation of immunotherapies for cancer remains the controlled modulation of the immune system, as these therapeutics have serious adverse effects including autoimmunity and nonspecific inflammation. Understanding how to increase the response rates to various classes of immunotherapy is key to improving efficacy and controlling these adverse effects. Advanced biomaterials and drug delivery systems, such as nanoparticles and the use of T cells to deliver therapies, could effectively harness immunotherapies and improve their potency while reducing toxic side effects. Here, we discuss these research advances, as well as the opportunities and challenges for integrating delivery technologies into cancer immunotherapy, and we critically analyse the outlook for these emerging areas.

Delivery technologies for cancer immunotherapy

Adeno-associated virus (AAV) is a promising gene vector based on a single-stranded (ss) DNA virus. Its transgene expression requires the conversion of ssDNA to double-stranded (ds) genome, a slow process responsible for the delayed transduction and occasional inefficiency. By mutating the inverted terminal repeat, we have made novel AAV vectors that predominantly package the self-complementary dsDNA genome. The dsAAV consistently demonstrated superior and accelerated transduction in vitro and in vivo. Dramatic increases in transgene expression were observed in most of the cell lines examined, including B16 melanoma and 3LL lung cancer that are difficult to be transduced by the conventional ssAAV vectors. Similar increases were also observed in vivo in a variety of tissues including muscle and liver. The dsAAV transduced a vast majority of the hepatocytes for more than 6 months, while the ssAAV transduced only a small fraction. In addition to circumventing the requirement for DNA synthesis, the dsAAV exhibited higher in vivo DNA stability and more effective circularization than the ssAAV, suggesting potential molecular mechanisms for the faster, stronger and prolonged transgene expression.

Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo.

Cationic lipids enhance siRNA-mediated interferon response in mice

miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenals, and intestine. FXR may play an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol. In this study, we report that FXR is also expressed in rat pulmonary artery endothelial cells (EC), a "nonclassical" bile acid target tissue. FXR is functional in EC, as demonstrated by induction of its target genes such as small heterodimer partner (SHP) after treatment with chenodeoxycholic acid, a FXR agonist. Interestingly, activation of FXR in EC led to downregulation of endothelin (ET)-1 expression. Reporter assays showed that activation of FXR inhibited transcriptional activation of the human ET-1 gene promoter and also repressed the activity of a heterologous promoter driven by activator protein (AP)-1 response elements. Electrophoretic mobility-shift and chromatin immunoprecipitation assays indicated that FXR reduced the binding activity of AP-1 transcriptional factors, suggesting that FXR may suppress ET-1 expression via negatively interfering with AP-1 signaling. These studies suggest that FXR may play a role in endothelial homeostasis and may serve as a novel molecular target for manipulating ET-1 expression in vascular EC.

Downregulation of Endothelin-1 by Farnesoid X Receptor in Vascular Endothelial Cells

Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represents an attractive approach to improve cancer therapy. However, the success of immunochemotherapy is hampered by the lack of a strategy to effectively co-deliver the two therapeutics to the tumours. Here we report the development of a dual-functional, immunostimulatory nanomicellar carrier that is based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumour immune suppression. An Fmoc group, an effective drug-interactive motif, is also introduced into the carrier to improve the drug loading capacity and formulation stability. We show that PEG2k-Fmoc-NLG alone is effective in enhancing T-cell immune responses and exhibits significant antitumour activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast cancer and melanoma mouse models.

/pdf/an-immunostimulatory-dual-functional-nanocarrier-that-24yzo2cvcw.pdf

Jiang Li

Papers

Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo.

Cationic lipids enhance siRNA-mediated interferon response in mice

miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression

Downregulation of Endothelin-1 by Farnesoid X Receptor in Vascular Endothelial Cells

An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy