A holistic analysis of the intrinsic and delivery-mediated toxicity of siRNA therapeutics.

Small interfering RNAs (siRNAs) are among the most promising therapeutic platforms in many life-threatening diseases. Owing to the significant advances in siRNA design, many challenges in the stability, specificity and delivery of siRNA have been addressed. However, safety concerns and dose-limiting toxicities still stand among the reasons for the failure of clinical trials of potent siRNA therapies, calling for a need of more comprehensive understanding of their potential mechanisms of toxicity. This review delves into the intrinsic and delivery related toxicity mechanisms of siRNA drugs and takes a holistic look at the safety failure of the clinical trials to identify the underlying causes of toxicity. In the end, the current challenges, and potential solutions for the safety assessment and high throughput screening of investigational siRNA and delivery systems as well as considerations for design strategies of safer siRNA therapeutics are outlined.

The quest for a better fight: How can nanomaterials address the current therapeutic and diagnostic obstacles in the fight against COVID-19?

The inexorable coronavirus disease 2019 (COVID-19) pandemic with around 226 million people diagnosed and approximately 4.6 million deaths, is still moving toward more frightening statistics, calling for the urgent need to explore solutions for the current challenges in therapeutic and diagnostic approaches. The challenges associated with existing therapeutics in COVID-19 include lack of in vivo stability, efficacy, and safety. Nanoparticles (NPs) can offer a handful of tools to tackle these problems by enabling efficacious and safe delivery of both virus- and host-directed therapeutics. Furthermore, they can enable maximized clinical outcome while eliminating the chance of resistance to therapy by tissue-targeting and concomitant delivery of multiple therapeutics. The promising application of NPs as vaccine platforms is reflected by the major advances in developing novel COVID-19 vaccines. Two of the most critical COVID-19 vaccines are mRNA-based vaccines delivered via NPs, making them the first FDA-approved mRNA vaccines. Besides, NPs have been deployed as simple, rapid, and precise tools for point of care disease diagnosis. Not enough said NPs can also be exploited in novel ways to expedite the drug discovery process. In light of the above, this review discusses how NPs can overcome the hurdles associated with therapeutic and diagnostic approaches against COVID-19.

Targeting non-apoptotic cell death in cancer treatment by nanomaterials: Recent advances and future outlook.

Many tumors develop resistance to most of the apoptosis-based cancer therapies. In this sense targeting non-apoptotic forms of cell death including necroptosis, autophagy and ferroptosis may have therapeutic benefits in apoptosis-defective cancer cells. Nanomaterials have shown great advantages in cancer treatment owing to their unique characteristics. Besides, the capability of nanomaterials to induce different forms of cell death has gained widespread attention in cancer treatment. Reports in this field reflect the therapeutic potential of necroptotic cell death induced by nanomaterials in cancer. Also, autophagic cell death induced by nanomaterials alone and as a part of chemo-, radio- and photothermal therapy holds great promise as anticancer therapeutic option. Besides, ferroptosis induction by iron-based nanomaterials in drug delivery, immunotherapy, hyperthermia and imaging systems shows promising results in malignancies. Hence, this review is devoted to the latest efforts and the challenges in this field of research and its clinical merits.

How can we develop better antispasmodics for irritable bowel syndrome?

INTRODUCTION: Irritable bowel syndrome (IBS) is a prevalent gastrointestinal (GI) disease. Antispasmodics are a heterogeneous group of drugs that tackle IBS-associated altered bowel habit and abdominal pain. However, some studies have shown their failure to exhibit benefit over placebo. Considering the place of antispasmodics in managing key symptoms of IBS, there is a growing need for developing more efficacious and safe antispasmodics. Areas covered: The authors discuss the role of rational drug design (RDD) in developing new antispasmodics with desired features. Furthermore, they review the potential pharmacological targets and herbal medicines with spasmolytic activity. In addition, the authors present the recent findings concerning novel mechanisms involved in GI motility modulation as well as the potential antispasmodic role of drugs used in other conditions. Expert opinion: To develop better antispasmodics, it will be essential to gain a deeper insight into the underlying mechanisms involved in IBS-induced dysmotility and to uncover GI-specific receptors that regulating motility. New antispasmodics with GI-restricted and the multi-targeting features can be developed via implementation of RDD. Furthermore, the modification of current antispasmodics by formulation technologies might expedite the development of better antispasmodics. To conclude, the complex nature of IBS means that future successful drug discovery will require a multi-disciplinary approach.

Emerging Roles of Probiotics in Prevention and Treatment of Breast Cancer: A Comprehensive Review of Their Therapeutic Potential.

Breast cancer is the most common cancer among women. Need for novel preventive and curative approaches with more safety than the present one seems inevitable. This review is devoted to potentially favorable role of probiotics in prevention and treatment of breast cancer as well as their alleviating role regarding chemotherapy-induced side effects. Literature was searched for human, animal, and in vitro studies about the role of probiotics in breast cancer. In vitro studies showed that probiotic intervention induces cancer cells apoptosis and inhibits their proliferation. In animal models, treatment with probiotics inhibited tumor growth and reduced tumor size; also, the immunomodulatory, antiangiogenesis and antimetastatic activities of probiotics were illustrated. Human studies showed that intake of Lactobacillus casei shirota reduced the breast cancer incidence and consumption of fermented milk products and yogurt was inversely associated with breast cancer incidence; however, no study regarding the curative role of probiotics in breast cancer is available. Studies on the effect of probiotics on chemotherapy-induced side effects in breast cancer were contradictory but showed potential for more investigation. Probiotics seem to have a potential role in both prevention and treatment of breast cancer. However, more clinical studies are needed to elucidate their efficacy and safety.