siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases

Abstract

RNAi (RNA interference)-based technology is emerging as a versatile tool which has been widely utilized in the treatment of various diseases. siRNA can alter gene expression by binding to the target mRNA and thereby inhibiting its translation. This remarkable potential of siRNA makes it a useful candidate, and it has been successively used in the treatment of diseases, including cancer. However, certain properties of siRNA such as its large size and susceptibility to degradation by RNases are major drawbacks of using this technology at the broader scale. To overcome these challenges, there is a requirement for versatile tools for safe and efficient delivery of siRNA to its target site. Lipid nanoparticles (LNPs) have been extensively explored to this end, and this paper reviews different types of LNPs, namely liposomes, solid lipid NPs, nanostructured lipid carriers, and nanoemulsions, to highlight this delivery mode. The materials and methods of preparation of the LNPs have been described here, and pertinent physicochemical properties such as particle size, surface charge, surface modifications, and PEGylation in enhancing the delivery performance (stability and specificity) have been summarized. We have discussed in detail various challenges facing LNPs and various strategies to overcome biological barriers to undertake the safe delivery of siRNA to a target site. We additionally highlighted representative therapeutic applications of LNP formulations with siRNA that may offer unique therapeutic benefits in such wide areas as acute myeloid leukaemia, breast cancer, liver disease, hepatitis B and COVID-19 as recent examples.

Potential of siRNA in COVID-19 therapy: Emphasis on in silico design and nanoparticles based delivery

“…The administration of naked siRNA for in vivo application is challenging due to various biological barriers such as degradation by RNAases, instability of the molecule and the immune response that could neutralize the siRNA and can cause other adverse effects ( Kalita et al, 2022 ). The carriers provide protection to the siRNA against biological factors and facilitate targeted delivery ( Zhang et al, 2022a ).…”

“…The accumulation of accumulation protons and counterions enhances the osmotic transportation of ions and water from the cytoplasm into the endosome. The rapid ionization at pKa values creates proton sponge effects resulting in osmotic swelling ( Kalita et al, 2022 ). The electrostatic interaction between the cationic lipids forming LNPs, and anionic lipids in the plasma membrane can further destabilize the endosomal membrane.…”

“…RNAi therapeutics have had a promising impact in reducing the expression of disease-associated genes ever since their discovery in 1990s ( Kalita et al, 2022 ). The field received its major breakthrough in 2018 with the approval of the first siRNA-based drug ‘Patisiran’ (Onpattro ® ) for the treatment of transthyretin-mediated amyloidosis ( Zhang et al, 2022a ).…”

“…The promising therapeutic benefits of siRNAs are overshadowed by the difficulty in attaining optimal biodistribution and pharmacokinetics of the RNAi therapeutic agents. Various intracellular hurdles, such as non-targeted accumulation in the liver/spleen, impaired long-term protein expression, immunological response, endosomal escape, and post-administration reactions, pose a significant challenge to siRNA therapy ( Kalita et al, 2022 ). To effectively counter such challenges, proper computational approach-based siRNA designing is deemed critical ( Idris et al, 2021 ).…”

Biodrug Delivery Systems: Do mRNA Lipid Nanoparticles Come of Age?

“…Despite being so powerful, LPN formulations still have major unsolved issues, including biological barriers to LPN delivery, tissue accumulation, the maintenance of prolonged protein expression, immunological responses, and endosomal escape (extensively reviewed in [39]). LNPs' surface charge is an additional feature that can be tailored for targeting abilities.…”