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PharmTech.com The Real Message Behind Commercial mRNA Products April eBook 2023 Pharmaceutical Technology ® 25 Development the design of unique lipids with improved properties (targeting, stability, tolerability)," she states. Data continues to be published on new lipid li- braries that demonstrate deliver y to different tis- sues/cells (1), Jung agrees. Targeting of mRNA-LNPs to specific tissues or cells can be achieved through either passive or active means. A majority of studies investigating ways to target LNPs have focused on passive targeting through modification of the LNP size, surface, and composition. Substitution or addi- tion of an extra moiety (polymeric or lipidic) has also been shown to be beneficial for achieving passive tar- geting toward specific organs, according to Mehta. "Active targeting approaches leverage conjugation of lipid components with small molecules, antibodies, proteins, or aptamers," Mehta comments. She points specifically to f lexible platforms and highlights the ASSET platform developed in the lab of Prof. Dan Peer at Tel Aviv University (2). "This type of approach en- ables customized targeting towards any cell receptor and, therefore, any tissue or organ," she says. Mehta does caution, however, that while there has been a tremendous push (and success) in this area over the past few years, there is still a long way to go and many challenges to overcome. Going beyond lipids While lipids have predominated the mRNA delivery space, they are not the only materials that can pro- vide effective delivery of these sensitive and highly charged drug substances. Hybrid lipid–polymer de- livery systems, for instance, have been developed to harness and combine the advantages of both lipid and polymer nanoparticles, according to Mehta. "Polymers possess an inherent high degree of chem- ical variety that is not feasible with lipids, increasing tremendously the possibilities of chemical functions, such as promoting endosomal escape, controlled re- leased of RNA, targeting, and finally stability," she explains. Lipids, meanwhile, show great potential for enhancing bioavailability, improving pharmacoki- netic profiles, and increasing biocompatibility. Strategies investigated to formulate hybrid systems include lipopolyplexes, hybrid LNPs, and others. As an example, Mehta notes that incorporation of bio- degradable polymers such as poly(beta amino esters) in LNP formulations leads to improved and specific lung delivery, highlighting the potential of hybrid lip- id-polymer nanoparticles (3). Evonik has a research agreement with Stanford Uni- versity to develop and commercialize the charge-alter- ing releasable transporter (CARTs) technology initially developed by the Waymouth lab. These polymeric ma- terials can effectively encapsulate mRNA and then rapidly degrade through controlled self-immolative reaction to release the mRNA, according to Jung. "T he f i rst generat ion of CA RTs showed m R NA deliver y efficacy in a range of cell types in both in vitro and in vivo models," Jung notes. He adds that subsequent generat ions of CA RTs incor porat ing lipid side chains on the CART backbone structure (4) showed an improved delivery efficiency. Further gen- erations of CARTs that are still under development, says Jung, have shown specific targeting capabilities in preliminary testing (5,6). References 1. Kularatne, R.N.; Crist, R.M.; Stern, S.T. The Future of Tissue-Targeted Lipid Nanoparticle-Mediated Nucleic Acid Delivery. Pharmaceuticals 2022, 15, 897. https://doi. org/10.3390/ph15070897 2. Kedmi, R.; Veiga, N; Ramishetti, S. Goldsmith, M.; Rosen- blum, R. et al. A Modular Platform for Targeted RNAi Therapeutics. Nature Nanotechnology 2018 13, pp. 214–219. https://doi.org/10.1038/s41565-017-0043-5. https://www. nature.com/articles/s41565-017-0043-5 3. Yan Cao; Zongxing He; Qimingxing Chen; Xiaoyan He; Lili Su, et al. Helper-Polymer Based Five-Element Nanoparti- cles (FNPs) for Lung-Specific mRNA Delivery with Long- Term Stability after Lyophilization. Nano Lett. 2022, 22, 16, 6580–6589. https://doi.org/10.1021/acs.nanolett.2c01784. https://pubs.acs.org/doi/10.1021/acs.nanolett.2c01784 4. McKinlay, C.J.; Vargas, J.R.; Blake, T.R.; and Waymouth, R.M. Charge-altering Releasable Transporters (CARTs) for the Deliver y and Release of mRNA in Living Ani- mals, PNAS, 2017, Jan. 9, 114 (4) E448-E456, https://doi. org/10.1073/pnas.1614193114 5. McKinlay, C.J.; Benner, N.L.; Haabeth, O.A; and Wender, P.A. Enhanced mRNA Delivery into Lymphocytes Enabled by Lipid-varied Libraries of Charge-altering Releasable Transporters, PNAS. 2018, June 11, 115 (26) E5859-E5866, https://doi.org/10.1073/pnas.1805358115 6. Haabeth, O. A. W.; Lohmeyer, J. J. K.; Sallets, A.; Blake, T.R.; Sagiv-Barfi, I. et al. An mRNA SARS-CoV-2 Vaccine Employing Charge-Altering Releasable Transporters with a TLR-9 Agonist Induces Neutralizing Antibodies and T Cell Memory. ACS Central Science 2021 7 (7), 1191-1204 DOI:10.1021/acscentsci.1c00361. ■ Interest in mRNA-LNP therapeutics and vaccines has risen dramatically from all perspectives.