Nanomedicine is a promising treatment strategy to target a range of diseases with limited side effects and complications. Although RNA (ribonucleic acid) molecules are fragile and can degrade quickly, new non-viral gene delivery approaches, such as nanoparticles, have the potential to deliver a range of RNA-based therapeutics and vaccines effectively. RNA-LNP (lipid nanoparticle) drugs, such as the Comirnaty (Pfizer BioNTech) and Spikevax (Moderna) COVID-19 vaccines, use lipids to deliver mRNA into cells protecting it from degradation and mediating a, safe and efficient intracellular delivery. With a slight alteration in the chemical structure of the ionizable lipid, choice of stabilizer, cholesterol, helper lipid, or the ratio of each component, novel applications, and modalities can be targeted. Therefore, choosing the right lipid composition can significantly impact biodistribution, efficacy, and pharmacokinetic profile and improve the drug’s safety. Also, selecting biocompatible and safe lipids is vital to minimize the risk of side effects as some lipids can be toxic to cells or cause an immune response in the body. Extensive scientific evidence supports the critical role of lipid optimization in developing RNA-LNP therapeutics, impacting efficiency, stability, safety, and tissue targeting1. Many studies have shown that modifying the lipid components of LNPs can improve delivery efficiency, reduce toxicity2,3, and affect immunogenicity and selective organ targeting, ultimately leading to accelerated clinical development timelines4.Research has also shown that incorporating lipids, such as cholesterol, can enhance nucleic acid delivery, intracellular uptake, and retention of LNPs5.

As observed, ionizable lipids hold a neutral charge under physiological pH to minimize toxicity and shifts charge with pH changes. Mixing ionizable lipids controls the ionization status of lipid nanoparticles, a factor responsible for targeted efficiency of LNP formulations. Ionizable lipid modifications can also improve the targeting and specificity of RNA-LNP drugs, improving their therapeutic efficacy6. Overall, these studies highlight the importance of LNP optimization for drug delivery and provide new insights into the impact of lipid composition on the efficacy and safety of RNA-LNP formulations. The Lipid Nanoparticles eBook offers an in-depth understanding of each component, emphasizing strategies to improve the LNP performance for proof-of-concept studies and clinical evaluation by carefully selecting and optimizing lipid properties. 

However, lipid formulation development can be time-consuming and expansive, especially with novel formulations or modalities. Lipids are a diverse class of molecules with a wide range of physiochemical properties, and their interactions with drug molecules are complex, affecting drug stability, bioavailability, and efficacy. Optimizing this interaction for results that meet regulatory requirements can involve extensive experimentation, testing, and documentation. Further, optimizing the lipid composition of LNPs for optimal performance, manufacturability and scalability is an important consideration. Some lipids may be challenging to source and require complex synthesis processes, impacting the production and manufacturing cost of RNA-LNP drugs.  Moreover, using preclinical lipid compositions for clinical use involves license agreements and intellectual property (IP) rights; obtaining such agreements can be complicated and time-consuming. In addition, these lipids' quality might fail to pass the stringent clinical standards. Therefore, sourcing the ionizable lipids that are of GMP quality and have scale-up production data can only enable its use for clinical applications under affordable licensing. The GMP lipids  undergo advanced analytical testing to understand their solubility, degradation behavior, and reactivity, ensuring specifications of the drug product remain consistent as production is scaled and, therefore, can be used for clinical purposes. Also, practical factors like storage and shelf-life are significant considerations, and studies have demonstrated that certain lipid modifications can improve the stability of LNPs and extend their shelf life7. To streamline the lipid formulation, drug developers can work with lipid formulation experts, use pre-optimized lipid mixes, and leverage advanced technologies, such as formulation screening, to accelerate formulation development and optimization.  

Streamline Screening with Pre-Optimized Off-The-Shelf LNP Formulations

 Pre-optimized lipid formulations undergo a rigorous optimization and are typically customized for specific drug or gene delivery systems. Its components are screened and optimized, and formulated to achieve optimal performance for a specific application. They are commercially available through off-the-shelf lipid nanoparticle reagent kits, which can be a practical choice for exploratory or early-stage research. Since these kits have already been tested and optimized for a particular application, it eliminates the need to screen and test different lipid formulations, which can be expensive. These lipid formulations are supported by the proof-of-concept (POC) data for safety and efficacy evaluation to assess the potentially toxic effects, such as cytotoxicity and immunogenicity, that enable lead candidates to advance quickly through screening and in vitro preclinical studies to fast-track in vivo clinical development. Further, pre-optimized formulations include stability testing that confirms the stability of the drug formulation under specific storage conditions and ensures that the drug remains safe and effective for the duration of its shelf life.   

In addition, pre-optimized lipids compositions can provide a baseline for comparison when testing new formulations. By comparing the performance of a new lipid formulation to a pre-optimized one, researchers can quickly assess whether the new formulation is an improvement or a step backward. Therefore, these off-the-shelf lipid formulations provide a standardized formulation, ensuring consistent and reproducible results across multiple batches; they also progress lead candidates quickly through preclinical stages and can be licensed for further clinical evaluation. 

Overall, pre-optimized lipid formulations simplify and accelerate the screening process and reduce costs by providing a validated and standardized lipid composition for drug delivery in a specific application. Precision NanoSystems’ off-the-shelf LNP kits are developed using high-quality raw materials and are subjected to rigorous quality control measures to ensure consistent results. Several options are available, so researchers can choose the appropriate lipid compositions that best suit their specific application requirements. Since protocols for the optimized applications are included, it is easy to use and does not require LNP formulation expertise to achieve optimal results. These LNP kits save time and are cost-effective when considering the time and effort saved using these pre-made formulations, ultimately fast-tracking the development of new nanomedicines by lowering the lipid barrier to entry so that any scientist can become a genomic medicine developer.  

Ionizable Lipid Portfolio

Beyond the pre-optimized formulations, it is also possible to customize LNP compositions through access to a well-characterized ionizable lipid portfolio. Collaborating with Precision NanoSystems to leverage our deep in-house expertise on ionizable lipid structures and properties, LNP formulation can be precisely optimized and rationally designed for maximum performance. Researchers can then quickly identify the most promising candidate, reducing the time and cost associated with synthesizing and testing individual lipids.  This also allows greater control over the physiochemical properties of the LNP, such as charge, size, and stability, and helps streamline the development process by reducing the number of iterations required to optimize the formulation for a specific drug candidate. Drug developers can confidently explore and develop formulations for personalized medicines by considering the patient's genetic profile, disease state, or other factors that impact the drug's efficacy and safety. 

Further, the ionizable lipid portfolio provides a standardized set of lipids, reducing variability in experimental results and enabling comparison between different studies. Therefore, it can be a valuable resource for researchers across fields or institutions, facilitating collaboration and knowledge sharing in developing lipid-based delivery systems. Access to an ionizable lipid portfolio can accelerate drug development by facilitating lipid selection, improving formulation efficiency, enhancing drug safety, and accelerating clinical translation. Precision NanoSystems' lipid portfolio is lowering the barrier to rapidly develop and optimize LNP-based drug delivery systems for clinical applications by providing researchers access to a diverse range of pre-screened lipid compositions. 

 Outlook

Since LNP formulations are highly complex, optimizing lipids and performing empirical testing is the only way to know the ideal formulation. The off-the-shelf lipid nanoparticle kits give an edge as they offer POC data, ensure scaling capabilities, and de-risk and accelerate scale-up. In addition, the lipids can be easily licensed for clinical evaluation, fast-tracking the drug development process. All of this can be achieved through collaboration with trusted industry experts offering scalable and validated lipids, expertise in formulation development, analytical testing, and regulatory support with a strong LNP development and manufacturing record. 

Partnering with industry leaders with a reputation for high-quality products in nanomedicine development that offer quality control testing, lipid stability data, scalability data, and analytics is a key advantage for drug development. Precision NanoSystems lipids and compositions integrate years of trusted nanoparticle expertise into pre-optimized formulations enabling any scientist to validate drug delivery quickly, fast-tracking clinical development and commercialization. Leverage our industry-recognized gold standard NanoAssemblr® platform while optimizing LNPs through our lipid portfolio. Our in-depth expertise in LNP formulations and partnerships greatly reduces the risk, time, and cost of moving to the clinic, accelerating the drug development of novel genomic medicines. We also offer service packages that include clinical support to perform analytical testing on lipid formulation to ensure quality and consistency that meet regulatory requirements throughout the drug development process.

Contact us to learn more about Precision NanoSystems’ Lipid Nanoparticle Portfolio.

Have questions about lipid formulations development? Learn more about formulation through our learning platform NanoMedU.

References:

1. Kulkarni, J.A. et al. (2021). Advances in lipid nanoparticle formulations for RNA-based gene therapy. Journal of Controlled Release, 330, 1092-1120. doi: 10.1016/j.jconrel.2021.02.013

2. Hou, X., Zaks, T., Langer, R. et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 6, 1078–1094 (2021). https://doi.org/10.1038/s41578-021-00358-0

3. Akinc, A. et al. (2010). Development of lipidoid-siRNA formulations for systemic delivery to the liver. Molecular Therapy, 18(4), 896-905. doi: 10.1038/mt.2010.16

4. Zukancic D, Suys EJA, Pilkington EH, Algarni A, Al-Wassiti H, Truong NP. The Importance of Poly(ethylene glycol) and Lipid Structure in Targeted Gene Delivery to Lymph Nodes by Lipid Nanoparticles. Pharmaceutics. 2020 Nov 9;12(11):1068. doi: 10.3390/pharmaceutics12111068. PMID: 33182382; PMCID: PMC7695259

5. Patel, S., Ashwanikumar, N., Robinson, E. et al. Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA. Nat Commun 11, 983 (2020). https://doi.org/10.1038/s41467-020-14527-2

6. Kaczmarek JC, Patel AK, Kauffman KJ, Fenton OS, Webber MJ, Heartlein MW, DeRosa F, Anderson DG. Polymer-Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs. Angew Chem Int Ed Engl. 2016 Oct 24;55(44):13808-13812. doi: 10.1002/anie.201608450. Epub 2016 Sep 30. PMID: 27690187; PMCID: PMC5279893.

Kon E, Elia U, Peer D. Principles for designing an optimal mRNA lipid nanoparticle vaccine. Curr Opin Biotechnol. 2022 Feb;73:329-336. doi: 10.1016/j.copbio.2021.09.016. Epub 2021 Oct 26. PMID: 34715546; PMCID: PMC8547895