2022 SACNAS Graduate Student Oral Presentation Award (Ester Álvarez Benedicto)

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Ester Álvarez Benedicto
UT Southwestern
Dallas, TX

Optimization of phospholipid chemistry for improved lipid nanoparticle (LNP) delivery of messenger RNA (mRNA)

Lipid nanoparticles (LNPs) have been established as an essential platform for nucleic acid delivery. Efforts have led to the development of vaccines that protect against SARS-CoV-2 infection using LNPs to deliver messenger RNA (mRNA) coding for the viral spike protein. Out of the four essential components that comprise LNPs, phospholipids represent an underappreciated opportunity for fundamental and translational study. We investigated this avenue by systematically modulating the identity of the phospholipid in LNPs with the goal of identifying specific moieties that directly enhance or hinder delivery efficacy. Results indicate that phospholipid chemistry can enhance mRNA delivery by increasing membrane fusion and enhancing endosomal escape. Phospholipids containing phosphoethanolamine (PE) head groups likely increase endosomal escape due to their fusogenic properties. Additionally, it was found that zwitterionic phospholipids mainly aided liver delivery, whereas negatively charged phospholipids changed the tropism of the LNPs from liver to spleen. These results demonstrate that the choice of phospholipid plays a role intracellularly by enhancing endosomal escape, while also driving organ tropism in vivo . These findings were then applied to Selective Organ Targeting (SORT) LNPs to manipulate and control spleen-specific delivery. Overall, selection of the phospholipid in LNPs provides an important handle to design and optimize LNPs for improved mRNA delivery and more effective therapeutics.

SACNAS National Diversity in STEM Conference, San Juan, Puerto Rico, October 27-29, 2022

  1. Cheng, Q, Farbiak, L, Vaidya, A, Guerrero, E, Lee, EE, Rose, EK, Wang, X, Robinson, J, Lee, SM, Wei, T et al.. In situ production and secretion of proteins endow therapeutic benefit against psoriasiform dermatitis and melanoma. Proc Natl Acad Sci U S A 2023; 120 (52): e2313009120. PubMed PMID:38109533 PubMed Central PMC10756300.
  2. Álvarez-Benedicto, E, Tian, Z, Chatterjee, S, Orlando, D, Kim, M, Guerrero, ED, Wang, X, Siegwart, DJ. Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma. Angew Chem Int Ed Engl 2023; 62 (44): e202310395. PubMed PMID:37651468 PubMed Central PMC10826899.
  3. Álvarez-Benedicto, E, Farbiak, L, Márquez Ramírez, M, Wang, X, Johnson, LT, Mian, O, Guerrero, ED, Siegwart, DJ. Optimization of phospholipid chemistry for improved lipid nanoparticle (LNP) delivery of messenger RNA (mRNA). Biomater Sci 2022; 10 (2): 549-559. PubMed PMID:34904974 PubMed Central PMC9113778.
  4. Farbiak, L, Cheng, Q, Wei, T, Álvarez-Benedicto, E, Johnson, LT, Lee, S, Siegwart, DJ. All-In-One Dendrimer-Based Lipid Nanoparticles Enable Precise HDR-Mediated Gene Editing In Vivo. Adv Mater 2021; 33 (30): e2006619. PubMed PMID:34137093 PubMed Central PMC10041668.
  5. Carballeira, NM, Morales-Guzman, C, Alvarez-Benedicto, E, Torres-Martinez, Z, Delgado, Y, Griebenow, KH, Tinoco, AD, Reguera, RM, Perez-Pertejo, Y, Carbajo-Andres, R et al.. First Total Synthesis of ω-Phenyl Δ6 Fatty Acids and their Leishmanicidal and Anticancer Properties. Curr Top Med Chem 2018; 18 (5): 418-427. PubMed PMID:29766807 PubMed Central PMC6994230.
  6. Hartman, EC, Jakobson, CM, Favor, AH, Lobba, MJ, Álvarez-Benedicto, E, Francis, MB, Tullman-Ercek, D. Quantitative characterization of all single amino acid variants of a viral capsid-based drug delivery vehicle. Nat Commun 2018; 9 (1): 1385. PubMed PMID:29643335 PubMed Central PMC5895741.
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Dana Crawford

Professor of Population and Quantitative Health Sciences and Associate Director of the Cleveland Institute for Computational Biology, with interest in pharmacogenomics, electronic health records, and diverse populations. Also, an avid foodie!