ABSTRACT
Introduction
Ionizable lipid nanoparticles (LNPs) have been proven to have high encapsulation, cellular uptake, and effective endosomal escape and are therefore promising for nucleic acid delivery. The combination of ionizable lipids, helper lipids, cholesterol, and PEG lipids advances nucleic acid-ionizable LNPs and distinguishes them from liposomes, SLNs, NLCs, and other lipid particles. Solvent injection and microfluidics technology are the primary manufacturing techniques for commercialized ionizable LNPs. Microfluidics technology limitations restrict the rapid industrial scale-up and therapeutic effectiveness of ionized LNPs. Alternative manufacturing technologies and target-specific lipids are urgently needed.
Area covered
This article provides an in-depth update on the lipid compositions, clinical trials, and manufacturing technologies for nucleic acid-ionizable LNPs. For the first time, we updated the distinction between ionizable LNPs and other lipid particles. We also proposed an alternate thermocycling technology for high industrial scale-up and the stability of nucleic acid-ionizing LNPs.
Expert opinion
Nucleic acid-ionizable LNPs have a promising future for delivering nucleic acids in a target-specific manner. Though ionizing LNPs are in their early stages, they face several challenges, including only hepatic delivery, a short shelf life, and ultra-cold storage. In our opinion, ligand-based, target-specific synthesized novel lipids and advanced manufacturing technologies can easily overcome the restrictions and open up a new approach for improved therapeutic efficacy for chronic disorders.
Graphical abstract
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Article highlights
Currently, ionizable LNPs are the key carriers for the delivery of siRNA and mRNA safely inside the body.
pH specific ionizable LNPs are structurally and functionally distinct from other lipid particles such as liposomes, SLN, and NLC.
The combination of ionizable lipids-helper lipids-cholesterol-PEG lipids is a distinguishing feature of currently commercialized ionizable LNPs and plays a specific role in nucleic acid bioavailability, stability, and circulation.
A large number of clinical trials suggest that target specific RNA (ribonucleic acid)-ionizable LNPs are the current trend to target diseases like cancer, Alzheimer’s, HIV and more chronic diseases.
Current manufacturing technologies for ionizable LNPs like solvent injection and microfluidics have their own advantages and limitations.
The limitation of microfluidics technology for the production of ionizable LNPs opens the door to a new thermocycling technological approach for formulation.
This box summarizes key points contained in the article.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.