Targeting Inflammasome Activation in COVID-19: Delivery of RNA Interference-Based Therapeutic Molecules

Abstract

Mortality and morbidity associated with COVID-19 continue to be significantly high worldwide, owing to the absence of effective treatment strategies. The emergence of different variants of SARS-CoV-2 is also a considerable source of concern and has led to challenges in the development of better prevention and treatment strategies, including vaccines. Immune dysregulation due to pro-inflammatory mediators has worsened the situation in COVID-19 patients. Inflammasomes play a critical role in modulating pro-inflammatory cytokines in the pathogenesis of COVID-19 and their activation is associated with poor clinical outcomes. Numerous preclinical and clinical trials for COVID-19 treatment using different approaches are currently underway. Targeting different inflammasomes to reduce the cytokine storm, and its associated complications, in COVID-19 patients is a new area of research. Non-coding RNAs, targeting inflammasome activation, may serve as an effective treatment strategy. However, the efficacy of these therapeutic agents is highly dependent on the delivery system. MicroRNAs and long non-coding RNAs, in conjunction with an efficient delivery vehicle, present a potential strategy for regulating NLRP3 activity through various RNA interference (RNAi) mechanisms. In this regard, the use of nanomaterials and other vehicle types for the delivery of RNAi-based therapeutic molecules for COVID-19 may serve as a novel approach for enhancing drug efficacy. The present review briefly summarizes immune dysregulation and its consequences, the roles of different non-coding RNAs in regulating the NLRP3 inflammasome, distinct types of vectors for their delivery, and potential therapeutic targets of microRNA for treatment of COVID-19.

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

“…Apoptosis represents a form of cell death of somatic cells long since known to be associated with abundant translocation of nuclear contents to cell surface blebs and ultimately, to the blood stream ( 195 – 197 ). Even more DAMPs are released when immune cells undergo inflammatory forms of cell death such as pyroptosis ( 22 , 58 , 181 , 198 , 199 ). The DAMP most frequently reported for COVID-19 is lactate dehydrogenase, a central enzyme of anaerobic glycolysis that is present in virtually all cells and that, therefore, reliably indicates cell death when occurring at high concentrations in the extracellular space ( 200 – 202 ).…”

Circulating microRNAs as emerging regulators of COVID-19

“…However, delivery of RNAi therapeutics is restricted because of charge density, molecular weight, and instability in the presence of nucleases 142 . Currently, distinct types of vectors to deliver RNAi-based therapeutics have been widely used to treat many diseases, including PEI, PLGA, Chitosan, PAMAM, Aptamer-dendrimer, and nanoparticles 143 . Mature miRNAs, together with Dicer and Argonaute proteins, form miRISC (miRNA-associated RNA-induced silencing complex) 144 , exist stably in blood and other body fluids in the form of EV wrapped or combined with proteins 145 .…”

COVID-19 inflammation and implications in drug delivery

“…DDS can be leveraged to load conventional anti-inflammatory drugs or gene therapies downregulating the cytokines expression to protect them, improve their physicochemical properties, control their release, optimize their pharmacokinetic profiles, and enhance their accumulation in the injury site [ [58] , [59] , [60] ]. More interestingly, novel DDS such as nanodecoys can directly bind proinflammatory cytokines antagonizing their action [ [61] , [62] , [63] ].…”