Understanding structure activity relationships of Good HEPES lipids for lipid nanoparticle mRNA vaccine applications

Goldman, Rebecca L.; Murthy, Namratha Turuvekere Vittala; Northen, Trent; Balakrishnan, Anuranjani; Chivukula, Sudha; Danz, Hillary; Tibbitts, Timothy; Dias, Anusha; Vargas, Jorel; Cooper, Dustin L.; Gopani, Hardip; Beaulieu, Angela; Kalnin, Kirill; Plitnik, Timothy; Karmakar, Saswata; Dasari, Ramesh; Landis, Ryan F.; Karve, Shrirang; DeRosa, Frank

doi:10.1016/j.biomaterials.2023.122243

Cited by 13 publications

(3 citation statements)

References 51 publications

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“…Interestingly, for RNA-LNPs a different pattern was observed with SM102-RNA > ALC0315-RNA > KC2-RNA suggesting that factors other than pKa, such as LNP morphology, inner structure, and RNA microenvironment, may account for the observed differences [40]. In another recent publication, the authors observed several lipid structure activity relationships that correlated with improved protein expression, including number of carbons on the lipid tails on the ester side and the effect of carbon spacing on the disulfide arm of the lipids [41]. The results of our study are consistent with a recent publication by Escalona-Rayo et al that demonstrated that SM102-RNA particles resulted in greater in vitro protein expression than ALC0315-RNA particles following transfection into mouse primary bone marrow dendritic cells [42].…”

Section: Discussionmentioning

confidence: 96%

The Expression Kinetics and Immunogenicity of Lipid Nanoparticles Delivering Plasmid DNA and mRNA in Mice

Zhang,

Pfeifle,

Lansdell

et al. 2023

Vaccines

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In recent years, lipid nanoparticles (LNPs) have emerged as a revolutionary technology for vaccine delivery. LNPs serve as an integral component of mRNA vaccines by protecting and transporting the mRNA payload into host cells. Despite their prominence in mRNA vaccines, there remains a notable gap in our understanding of the potential application of LNPs for the delivery of DNA vaccines. In this study, we sought to investigate the suitability of leading LNP formulations for the delivery of plasmid DNA (pDNA). In addition, we aimed to explore key differences in the properties of popular LNP formulations when delivering either mRNA or DNA. To address these questions, we compared three leading LNP formulations encapsulating mRNA- or pDNA-encoding firefly luciferase based on potency, expression kinetics, biodistribution, and immunogenicity. Following intramuscular injection in mice, we determined that RNA-LNPs formulated with either SM-102 or ALC-0315 lipids were the most potent (all p-values < 0.01) and immunogenic (all p-values < 0.05), while DNA-LNPs formulated with SM-102 or ALC-0315 demonstrated the longest duration of signal. Additionally, all LNP formulations were found to induce expression in the liver that was proportional to the signal at the injection site (SM102: r = 0.8787, p < 0.0001; ALC0315: r = 0.9012, p < 0.0001; KC2: r = 0.9343, p < 0.0001). Overall, this study provides important insights into the differences between leading LNP formulations and their applicability to DNA- and RNA-based vaccinations.

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Section: Discussionmentioning

confidence: 96%

The Expression Kinetics and Immunogenicity of Lipid Nanoparticles Delivering Plasmid DNA and mRNA in Mice

Zhang,

Pfeifle,

Lansdell

et al. 2023

Vaccines

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show abstract

“…Combinatorial lipid synthesis via enzymatic formation of ester bonds is a novel, green, alternative strategy that has yielded a highly potent mRNA vaccine candidate ( 59 ). Using an ionizable core of the 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer and combinatorial addition of multiple tails also produced a potent mRNA vaccine candidate that showed good activity in NHPs ( 60 ).…”

Section: Progress In Nanoparticle Chemistrymentioning

confidence: 99%

Recent advances in nanoparticulate RNA delivery systems

Witten,

Hu,

Langer

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Nanoparticle-based RNA delivery has shown great progress in recent years with the approval of two mRNA vaccines for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and a liver-targeted siRNA therapy. Here, we discuss the preclinical and clinical advancement of new generations of RNA delivery therapies along multiple axes. Improvements in cargo design such as RNA circularization and data-driven untranslated region optimization can drive better mRNA expression. New materials discovery research has driven improved delivery to extrahepatic targets such as the lung and splenic immune cells, which could lead to pulmonary gene therapy and better cancer vaccines, respectively. Other organs and even specific cell types can be targeted for delivery via conjugation of small molecule ligands, antibodies, or peptides to RNA delivery nanoparticles. Moreover, the immune response to any RNA delivery nanoparticle plays a crucial role in determining efficacy. Targeting increased immunogenicity without induction of reactogenic side effects is crucial for vaccines, while minimization of immune response is important for gene therapies. New developments have addressed each of these priorities. Last, we discuss the range of RNA delivery clinical trials targeting diverse organs, cell types, and diseases and suggest some key advances that may play a role in the next wave of therapies.

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“…[4][5][6] The chemical structure of the ionizable lipid is critical to the delivery efficiency of mRNA, which directly impacts protein output and vaccine efficacy. [7][8][9][10] Ionizable lipids are carefully designed such that LNPs have a neutral surface charge at physiological pH and then become positively charged in acidic conditions, facilitating both mRNA encapsulation and endosomal escape. While LNPs are currently the most potent and well-tolerated delivery system for mRNA, new ionizable lipid chemistry may further improve the efficacy and tolerability of mRNA vaccines.…”

Section: Introductionmentioning

confidence: 99%

Engineering ionizable lipids for rapid biodegradation balances mRNA vaccine efficacy and tolerability

Couture-Senécal,

Tilstra,

Khan

2024

Preprint

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The optimization of lipid nanoparticles (LNPs) has played a key role in enhancing the efficacy of mRNA vaccines, yet challenges with LNP tolerability remain. The ionizable lipid component within LNPs is critical to the efficient delivery of mRNA. Ionizable lipids can also trigger innate immune activation, which is beneficial for vaccine efficacy but may contribute to adverse inflammatory reactions. Engineering ionizable lipids for rapid biodegradation is a promising, yet underexplored, strategy to dampen inflammation. Here, we report the rational design and optimization of biodegradable ionizable lipids for intramuscular mRNA vaccines in mice. We show that in vivo biodegradability is enhanced by controlling lipid hydrolysis kinetics and that protein output is maximized by tuning the LNP apparent pKa. In an influenza vaccine model, the lead lipid (δO3) generates equivalent neutralizing antibodies and stronger antigen-specific T cell responses compared to a benchmark lipid (SM-102) used in approved mRNA vaccines. Furthermore, by comparing ionizable lipid analogs with similar potency but opposing biodegradation kinetics, we find that faster lipid clearance from tissues coincides with a lower inflammatory response while preserving strong vaccine immunogenicity. These findings demonstrate that fast-degrading ionizable lipids can balance the efficacy and tolerability of mRNA vaccines, with implications for addressing side effects and patient acceptance of new vaccine applications.

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Understanding structure activity relationships of Good HEPES lipids for lipid nanoparticle mRNA vaccine applications

Cited by 13 publications

References 51 publications

The Expression Kinetics and Immunogenicity of Lipid Nanoparticles Delivering Plasmid DNA and mRNA in Mice

The Expression Kinetics and Immunogenicity of Lipid Nanoparticles Delivering Plasmid DNA and mRNA in Mice

Recent advances in nanoparticulate RNA delivery systems

Engineering ionizable lipids for rapid biodegradation balances mRNA vaccine efficacy and tolerability

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