Recent advances in nanocomposite-based delivery systems for targeted CRISPR/Cas delivery and therapeutic genetic manipulation.

CRISPR/Cas systems are novel gene editing tools with tremendous capacity and accuracy for gene editing and hold great potential for therapeutic genetic manipulation. However, the lack of safe and efficient delivery methods for CRISPR/Cas and its guide RNA hinders their wide adoption for therapeutic applications. To this end, there is an increasing demand for safe, efficient, precise, and non-pathogenic delivery approaches, both in vitro and in vivo. With the convergence of nanotechnology and biomedicine, functional nanocomposites have demonstrated unparalleled sophistication to overcome the limits of CRISPR/Cas delivery. The tunability of the physicochemical properties of nanocomposites makes it very easy to conjugate them with different functional substances. The combinatorial application of diverse functional materials in the form of nanocomposites has shown excellent properties for CRISPR/Cas delivery at the target site with therapeutic potential. The recent highlights of selective organ targeting and phase I clinical trials for gene manipulation by CRISPR/Cas after delivery through LNPs are at the brink of making it to routine clinical practice. Here we summarize the recent advances in delivering CRISPR/Cas systems through nanocomposites for targeted delivery and therapeutic genome editing.

Therapeutic Potentials of MicroRNAs for Curing Diabetes Through Pancreatic ß-Cell Regeneration or Replacement.

MicroRNAs are a type of noncoding RNAs that regulates the expression of target genes at posttranscriptional level. MicroRNAs play essential roles in regulating the expression of different genes involved in pancreatic development, ß-cell mass maintenance, and ß-cell function. Alteration in the level of miRNAs involved in ß-cell function leads to the diabetes. Being an epidemic, diabetes threatens the life of millions of patients posing a pressing demand for its urgent resolve. However, the currently available therapies are not substantial to cure the diabetic epidemic. Thus, researchers are trying to find new ways to replenish the ß-cell mass in patients with diabetes. One promising approach is the in vivo regeneration of ß-cell mass or increasing the efficiency of ß-cell function. Another clinical strategy is the transplantation of in vitro developed ß-like cells. Owing to their role in pancreatic ß-cell development, maintenance, functioning and their involvement in diabetes, overexpression or attenuation of different miRNAs can cause ß-cell regeneration in vivo or can direct the differentiation of various kinds of stem/progenitor cells to ß-like cells in vitro. Here, we will summarize different strategies used by researchers to investigate the therapeutic potentials of miRNAs, with focus on miR-375, for curing diabetes through ß-cell regeneration or replacement.

Gimmicks of gamma-aminobutyric acid (GABA) in pancreatic ß-cell regeneration through transdifferentiation of pancreatic α- to ß-cells.

In vivo regeneration of lost or dysfunctional islet ß cells can fulfill the promise of improved therapy for diabetic patients. To achieve this, many mitogenic factors have been attempted, including gamma-aminobutyric acid (GABA). GABA remarkably affects pancreatic islet cells' (α cells and ß cells) function through paracrine and/or autocrine binding to its membrane receptors on these cells. GABA has also been studied for promoting the transformation of α cells to ß cells. Nonetheless, the gimmickry of GABA-induced α-cell transformation to ß cells has two different perspectives. On the one hand, GABA was found to induce α-cell transformation to ß cells in vivo and insulin-secreting ß-like cells in vitro. On the other hand, GABA treatment showed that it has no α- to ß-cell transformation response. Here, we will summarize the physiological effects of GABA on pancreatic islet ß cells with an emphasis on its regenerative effects for transdifferentiation of islet α cells to ß cells. We will also critically discuss the controversial results about GABA-mediated transdifferentiation of α cells to ß cells.

Pancreatic ß-cell replacement: advances in protocols used for differentiation of pancreatic progenitors to ß-like cells.

Insulin-producing cells derived from in vitro differentiation of stem cells and non-stem cells by using different factors can spare the need for genetic manipulation and provide a cure for diabetes. In this context, pancreatic progenitors differentiating to ß-like cells garner increasing attention as ß-cell replacement source. This kind of cell therapy has the potential to cure diabetes, but is still on its way of being clinically useful. The primary restriction for in vitro production of mature and functional ß-cells is developing a physiologically relevant in vitro culture system which can mimic in vivo pathways of islet development. In order to achieve this target, different approaches have been attempted for the differentiation of pancreatic stem/progenitor cells to ß-like cells. Here, we will review some of the state-of-the-art protocols for the differentiation of pancreatic progenitors and differentiated pancreatic cells into ß-like cells with a focus on pancreatic duct cells.