Figure 1.Fit-for-purpose lipids can accelerate RNA-LNP drug development

The recent approval and massive administration of Pfizer/BioNTech and Moderna mRNA vaccines have rapidly accelerated the clinical validation of RNA-Lipid Nanoparticle (LNP) therapeutics. Emerging biotech companies are investing in novel delivery capabilities to address the needs of different modalities and extra-hepatic delivery. For RNA-LNP drugs, the drug delivery foundation is only as strong as the lipid formulation. Lipids are functional excipients that play a significant role in tailoring the lipid nanoparticles for drug delivery. The lipid component of an LNP can be optimized for structural properties and additional functionalities such as targeting and immunomodulation and is essential for clinical translation. They promote key LNP features and influence nucleic acid protection, formulation stability, and drug release. Therefore, lipids play a crucial role in lipid-based RNA therapeutics scaling through clinical development to commercialization. 

As drug development is lengthy and costly, developing new formulations including novel lipids, at the discovery stage is required. Rapid validation of lipids drives growth in the genomic medicine toolbox to encapsulate varied payloads, target different cell types and tissues, and manufacture products at various scales. Access to quality lipids and optimization expertise can provide a competitive advantage and accelerate development and manufacturing by reducing the number of lipid formulation steps, simplifying the process, and reducing costs.

One example is Doxil®, which iteratively improved formulation design and lipids with additional functionalities to ensure robust manufacturing methods, higher encapsulation efficiencies, better drug accumulation at the target site, and fewer dose-limiting toxicities ¹. In another example, Anderson and colleagues demonstrated that an alkyne ionizable lipid (A6) could significantly increase membrane fusion and facilitate albumin-mediated mRNA delivery when incorporated into benchmark LNPs (e.g., MC3)². These examples indicate that rational design and lipids screening are necessary for potent RNA delivery. Thus, to start with an end in mind, follow the steps below to accelerate the delivery of commercial nanomedicines.

1. Develop Fit-For-Purpose Lipids - LNP formulations are not One-Size-Fits-All. Several studies have highlighted that LNP formulations optimized for siRNA delivery are unsuitable for other payloads like mRNA and DNA². However, the formulations can be optimized at the earliest stages so that it is Fit-For-Purpose. Optimization can be labor-intensive, but with access to a lipid nanoparticle portfolio, the developers can reach the full potential of nucleic acid therapeutics across applications. Many companies have started working on experimental formulations, notably Replicate Bioscience entered a licensing agreement with Precision NanoSystems to access the full lipid nanoparticle solution, including the proprietary lipid library. Accessing the lipid library will allow Replicate Bioscience to develop novel drug candidates fit for the company's lead programs and de-risk and accelerate drug program development.

2. Lipid Validation Data and Performance Criteria – Therapeutically relevant application-based screening can identify lipids and LNP compositions for specific applications. Developing the right analytics from the discovery stage saves significant time for validation and lowers the risk of developing a bespoke lipid nanoparticle formulation, accelerating preclinical programs. To achieve this, procure lipids with proven validation data, and lipid nanoparticle portfolio comprising more than 100 lipids with diverse pKa and biodegradability for different applications. Proof of concept (POC) data sets of Precision NanoSystems enabling Cell Therapy, Gene Therapy (Protein Replacement), and Vaccine applications showcase the capabilities of these lipids.

3. Lipids Safety and Tolerability – To avoid unexpected setbacks, consider checking the lipids' safety and toxicity at earlier stages. Recently, a class of multi-tail ionizable phospholipids was developed; the best-performing 9A1P9 aided in membrane instability and cargo release, considerably improving LNP-mediated tissue-selective mRNA delivery and gene editing³. However, because lead multi-tail ionizable lipids often have stable backbones and limited degradability, their toxicity and immunogenicity should always be considered and validating lipid safety data at the earliest stages is crucial. Look for lipids with safety and tolerability data like the recent NHP study to evaluate the immunogenicity of saRNA-LNP COVID vaccine candidates in non-naive rhesus primate models highlights the safety of one of its lipid formulations, PNI-002.

4. Scalable Lipids - Clinical ionizable lipids are all synthesized in multiple steps trying countless variations on various lipid combinations, posing scalability challenges. Thus, always consider scalability, the economy of scale, and batch size while selecting lipids early in drug development as the end goal of commercialization is achievable with the right strategies. For successful manufacturing and scale-up, along with access to a well-characterized lipid nanoparticle portfolio to identify the lead formulation, confirm and invest in lipids that enable the clinical use of such lead formulation. Learn about Precision NanoSystems RUO, GLP and GMP lipids accessible through off-the-shelf kits and lipid licenses aligned with emerging biotech needs, allowing early access to lipids that can scale.

5. Lipid Licensing – Achieving optimal formulation is a complex task but once optimized for one target organ, the mRNA payload can be changed with minimal optimization, and the nanoparticle can be used repeatedly for similar targeted applications. Precision NanoSystems help accelerate customers' genomic medicine programs to IND submission through unique and easy-to-use LNP RUO kits and proprietary lipids owned by the company and offered under affordable licensing to be used for clinical/commercial applications.

The end goal is to build a strong foundation that significantly reduces the risk, time, and cost of moving to the clinic. Certainly, access to quality lipids and continuous synthesis and screening of functionalized lipids by chemically optimizing their molecular structures can promote the development of more versatile, highly efficient, and biocompatible delivery vehicles. But the formulation medium influences the self-assembly process and encapsulation efficiency, and the formulation method influences the lipid nanoparticles' properties, quality, and efficacy. Thus, nanoparticle delivery technologies are also central to developing genomic medicines.

About Precision NanoSystems

Precision NanoSystems has strong IP and technical expertise in continuous flow microfluidic mixing technologies, instruments, lipid reagents, and clinical nanoparticle development that provides an end-to-end solution to accelerate genomic medicine development. In addition, Precision NanoSystems, now part of the Danaher group of companies, has a track record of enabling discovery, formulation development/optimization, scale-up, and GMP manufacturing for its preclinical and clinical customers, including innovative labs and emerging biotechs.

If you need help with a lipid-based drug delivery problem, please contact Precision NanoSystems and learn more about the Lipid Nanoparticle Portfolio.

Have questions about lipid formulations development? Learn more about formulation here.

References:

1. Miao, L., Lin, J., Huang, Y. et al. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat Commun 11, 2424 (2020). https://doi.org/10.1038/s41467-020-16248-y

2. Hald Albertsen C, Kulkarni JA, Witzigmann D, Lind M, Petersson K, Simonsen JB. The role of lipid components in lipid nanoparticles for vaccines and gene therapy. Adv Drug Deliv Rev. 2022 Sep;188:114416. doi: 10.1016/j.addr.2022.114416. Epub 2022 Jul 3. PMID: 35787388; PMCID: PMC9250827.

3. Liu, S., Cheng, Q., Wei, T. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 20, 701–710 (2021). https://doi.org/10.1038/s41563-020-00886-0