Lipid‐based nucleic acid therapeutics with in vivo efficacy

Abstract

Synthetic vectors for therapeutic nucleic acid delivery are currently competing significantly with their viral counter parts due to their reduced immunogenicity, large payload capacity, and ease of manufacture under GMP‐compliant norms. The approval of Onpattro, a lipid‐based siRNA therapeutic, and the proven clinical success of two lipid‐based COVID‐19 vaccines from Pfizer‐BioNTech, and Moderna heralded the specific advantages of lipid‐based systems among all other synthetic nucleic acid carriers. Lipid‐based systems with diverse payloads—plasmid DNA (pDNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), and messenger RNA (mRNA)—are now becoming a mature technology, with growing impact in the clinic. Research over four decades identified the key factors determining the therapeutic success of these multi‐component systems. Here, we discuss the main nucleic acid‐based technologies, presenting their mechanism of action, delivery barriers facing them, the structural properties of the payload as well as the component lipids that regulate physicochemical properties, pharmacokinetics and biodistribution, efficacy, and toxicity of the resultant nanoparticles. We further detail on the formulation parameters, evolution of the manufacturing techniques that generate reproducible and scalable outputs, and key manufacturing aspects that enable control over physicochemical properties of the resultant particles. Preclinical applications of some of these formulations that were successfully translated from in vitro studies to animal models are subsequently discussed. Finally, clinical success and failure of these systems starting from 1993 to present are highlighted, in a holistic literature review focused on lipid‐based nucleic acid delivery systems. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

Mechanisms and research advances in mRNA antibody drug-mediated passive immunotherapy

“…Despite the advantages of mRNA antibodies, the mRNA delivery technology was not originally designed for passive immunotherapy. After almost > 30 years of development, mRNA biologics are being developed primarily for prophylactic vaccination against certain potentially infectious diseases or cancer [ 164 ]. The most typical case is COVID-19 prevention using the mRNA vaccines.…”

Nucleotides Entrapped in Liposome Nanovesicles as Tools for Therapeutic and Diagnostic Use in Biomedical Applications

“…Regarding the use of nucleotides, as carried molecules, liposomes are used [ 1 ] to maintain the integrity of nucleotide sequences, to increase their half-life in biological media, and [ 4 ] to facilitate their transport across biological membranes, thus optimizing the pharmacokinetic profile of these biomolecules. For this third application, it is important to highlight that as hydrophilic and polar molecules, the nucleotides usually have a low transport rate through biological membranes [ 5 ].…”

“…Moreover, in comparison to other nucleotide transporters, such as viral vectors, lipid nanocarriers have some additional advantages ( Figure 2 ). In terms of immunogenicity, liposomes, or alternative lipid carriers, may have reduced immunogenicity, in comparison to these conventional viral carriers [ 5 ]. The development of these nanocarriers was also a response to the replacement of these other types of nucleotide carriers, which normally go through biotechnological manufacturing routes.…”