In the past few years, there has been increasing focus on the use of messenger RNA (mRNA) as a new therapeutic modality. Current clinical efforts encompassing mRNA-based drugs are directed toward infectious disease vaccines, cancer immunotherapies, therapeutic protein replacement therapies, and treatment of genetic diseases. However, challenges that impede the successful translation of these molecules into drugs are that (i) mRNA is a very large molecule, (ii) it is intrinsically unstable and prone to degradation by nucleases, and (iii) it activates the immune system. Although some of these challenges have been partially solved by means of chemical modification of the mRNA, intracellular delivery of mRNA still represents a major hurdle. The clinical translation of mRNA-based therapeutics requires delivery technologies that can ensure stabilization of mRNA under physiological conditions. Here, we (i) review opportunities and challenges in the delivery of mRNA-based therapeutics with a focus on non-viral delivery systems, (ii) present the clinical status of mRNA vaccines, and (iii) highlight perspectives on the future of this promising new type of medicine.

RNA interference (RNAi) has an unprecedented potential as a therapeutic strategy for reversibly silencing the expression of any gene. Therapeutic delivery of the RNAi mediator, i.e., small interfering RNA (siRNA), can be used to address diseases characterized by gene overexpression, for example inflammatory conditions like chronic obstructive pulmonary disease (COPD). Macrophages play a key role in COPD pathogenesis and are recruited to the airways and lung parenchyma, where they release proinflammatory cytokines, e.g., tumor necrosis factor-alpha (TNF-α). Hence, targeting TNF-α with siRNA is a promising therapeutic approach for COPD management. However, a safe and effective delivery system is required for delivery of TNF-α siRNA into the cytosol of hard-to-transfect macrophages. The purpose of this study was to optimize the intracellular delivery of TNF-α siRNA to the lipopolysaccharide-activated murine macrophage cell line RAW 264.7 using lipidoid-polymer hybrid nanoparticles (LPNs) composed of the lipid-like transfection agent lipidoid 5 (L₅) and the biodegradable polymer poly (D,L-lactide-co-glycolide). Applying a quality-by-design approach, the influence of critical formulation variables, i.e., the L₅content and the L₅:siRNA ratio (w/w), on critical quality attributes (CQAs) was investigated systematically using risk assessment and design of experiments, followed by delineation of an optimal operating space (OOS). The CQAs were identified based on the quality target product profile and included size, polydispersity index, zeta potential, encapsulation efficiency and loading for achieving efficient and safe TNF-α gene silencing in activated RAW 264.7 cells. Formulations inducing efficient gene silencing and low cytotoxicity were identified, and the optimal formulations displayed L₅contents of 15 and 20% (w/w), respectively, and an L₅:siRNA weight ratio of 15:1. All tested formulations within the OOS mediated efficient and sequence-specific TNF-α gene silencing in RAW 264.7 cells at TNF-α-siRNA concentrations, which were significantly lower than the concentrations required of non-encapsulated TNF-α-siRNA, highlighting the benefit of the delivery system. The results also demonstrate that increasing the loading of siRNA into the delivery system does not necessarily imply enhanced gene silencing. This opens new avenues for further exploitation of LPNs as a robust platform technology for delivering TNF-α siRNA to macrophages, e.g., in the management of COPD.

Nanotechnology is an area of growing public interest. Employing nanotechnology in the field of drug delivery has led to the advent of nanopharmaceuticals. Nanopharmaceuticals are bound to surmount various obstacles that the field of pharmacy is currently facing by offering various advantages thereby, a promising potential to formulate advanced medicines with fewer adverse effects. Extensive research is in place, thus instigating the development of novel drug delivery systems, such as carbon nanotubes, nanosponges, nano wafers, and nanofibers, to name a few. Since their inception, these nanopharmaceuticals have advanced significantly regarding their preparation strategy and scope of applications. This article aims to review the merits, limitations, and scope of these aforementioned delivery systems.

Objective: The objective of this research was to explore the potential of Hot Melt Extrusion (HME) technique by using theophylline as the model drug to produce sustained release tablets utilizing Compritol^®888 ATO as the retarding material and to study the influence of lipid: excipient ratio, excipient type as well as the processing conditions of the extruder on the release profile. Methods: The tablets prepared using hot fusion method was compared to the ones concocted by the HME technology. During the HME process, a powder mixture of moisture-free drug, lipid, and other adjuncts was introduced into the extruder and liquefied inside the barrel of the extruder. The in vitro dissolution studies of the formulations were carried out in pH 7.2 buffer using USP Apparatus 2. The extrudates were characterized via differential scanning calorimetry. Results: Comparing the two methods of processing, it was observed by the dissolution studies using phosphate buffer pH 7.2, that the tablets prepared by Hot Melt Extrusion method had a higher extent of release where all 3 formulations crossed 80% at the 8-hour mark, whereas the tablets prepared by hot fusion method did not show such consistency. Conclusion: This study demonstrated the fact that Compritol^®888 ATO is a suitable waxy material that can be used as a matrix-forming agent to control the release of theophylline using the Hot Melt Extrusion process.