Abstract Details

This review aims to discuss in detail the recent advancements in the design and delivery of mRNA and pDNA using lipid and polymer-based nanoparticles. As both mRNA and pDNA possess great potential for therapeutic applications in gene therapy, vaccines, cancer, and regenerative medicine, several challenges are associated with their clinical applications, including degradation by nucleases, low cellular uptake, poor intracellular trafficking, sequestration in endosomes, and toxicity to cells. To address these challenges, LNPs and polymer-based nanoparticles have been explored extensively as non-viral gene delivery systems for the protection and efficient delivery of both mRNA and pDNA into cells. Lipid nanoparticles, particularly those containing ionizable lipids, a variety of helper lipids, including cholesterol and phospholipids, and PEG-conjugated lipids, have been explored in detail to modulate the stability, cellular uptake, and endosomal escape of the nanoparticles. In addition to these lipids, a variety of polymeric systems, such as PEI, PLGA, chitosan, and biodegradable poly(beta-amino esters), have been investigated for their ability to encapsulate nucleic acids, to be biocompatible, and to facilitate the controlled release of both mRNA and pDNA. The delivery of both mRNA and pDNA by these nanoparticles is influenced by several critical parameters, including size, surface charge, lipid/polymer composition, architecture of polymeric carriers, and the efficiency of loading with high concentrations of both mRNA and pDNA. This paper also aims to address the differences in requirements for the efficient delivery of mRNA and pDNA, including the need for cytoplasmic release of mRNA and nuclear import of pDNA. The latest advances in the development of biodegradable materials, targeted delivery, and hybrid lipid/polymer-based systems are also studied to identify the potential for improvements in terms of delivery efficiency, reduced toxicity, and reduced immunogenicity. However, several major challenges, including tissue-specific delivery, endosomal escape, scalability of manufacture, and the safety of long-term delivery of both mRNA and pDNA, need to be addressed.

References

1. M. Hannig and A. Joiner, “The structure, function and properties of the acquired pellicle,” Monographs in Oral Science, vol. 19, pp. 29–64, 2006. DOI: 10.1159/000090585.

2. C. Hannig and M. Hannig, “The oral cavity—a key system to understand substratum-dependent bioadhesion on solid surfaces in man,” Clinical Oral Investigations, vol. 13, no. 2, pp. 123–139, 2009. DOI: 10.1007/s00784-008-0243-3.

3. P. E. Kolenbrander, R. J. Palmer Jr., S. Periasamy, and N. S. Jakubovics, “Oral multispecies biofilm development and the key role of cell–cell distance,” Nature Reviews Microbiology, vol. 8, pp. 471–480, 2010. DOI: 10.1038/nrmicro2381.

4. C. Hannig, M. Hannig, and T. Attin, “Enzymes in the acquired enamel pellicle,” European Journal of Oral Sciences, vol. 113, no. 1, pp. 2–13, 2005. DOI: 10.1111/j.1600-0722.2004.00180.x.

5. C. Hannig, M. Hannig, O. Rehmer, G. Braun, E. Hellwig, and A. Al-Ahmad, “Fluorescence microscopic visualization and quantification of initial bacterial colonization on enamel in situ,” Archives of Oral Biology, 2007. DOI: 10.1016/j.archoralbio.2007.05.006.

6. S. Liu, T. H. Zeng, M. Hofmann, E. Burcombe, J. Wei, R. Jiang, J. Kong, and Y. Chen, “Antibacterial activity of graphite, graphite oxide, graphene oxide, and reduced graphene oxide: Membrane and oxidative stress,” ACS Nano, vol. 5, no. 9, 2011. DOI: 10.1021/nn202451x.

7. L. Liu, J. Liu, Y. Wang, X. Yan, and D. D. Sun, “Facile synthesis of monodispersed silver nanoparticles on graphene oxide sheets with enhanced antibacterial activity,” New Journal of Chemistry, vol. 35, p. 1418, 2011. DOI: 10.1039/C1NJ20076C.

8. W. Hu, C. Peng, W. Luo, M. Lv, X. Li, D. Li, Q. Huang, and C. Fan, “Graphene-based antibacterial paper,” ACS Nano, vol. 4, no. 7, pp. 4317–4323, 2010. DOI: 10.1021/nn101097v.

9. P. D. Marsh, “Dental plaque as a microbial biofilm,” Caries Research, vol. 38, no. 3, pp. 204–211, 2004. DOI: 10.1159/000077756.

10. P. D. Marsh, “Dental plaque: Biological significance of a biofilm and community life-style,” Journal of Clinical Periodontology, vol. 32, suppl. 6, pp. 7–15, 2005. DOI: 10.1111/j.1600-051X.2005.00790.x.

11. P. D. Marsh, “Dental plaque as a biofilm and a microbial community—Implications for health and disease,” BMC Oral Health, vol. 6, suppl. 1, article S14, 2006. DOI: 10.1186/1472-6831-6-S1-S14.

12. H.-C. Flemming, J. Wingender, U. Szewzyk, P. Steinberg, S. A. Rice, and S. Kjelleberg, “Biofilms: An emergent form of bacterial life,” Nature Reviews Microbiology, vol. 14, no. 9, pp. 563–575, 2016. DOI: 10.1038/nrmicro.2016.94.

13. V. Palmieri, M. C. Lauriola, G. Ciasca, C. Conti, M. De Spirito, and M. Papi, “The graphene oxide contradictory effects against human pathogens,” Nanotechnology, vol. 28, no. 15, article 152001, 2017. DOI: 10.1088/1361-6528/aa6150.