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Cited by 1,018Nanoparticle-Based Drug DeliveryRNA Interference and Gene DeliveryAdvanced Drug Delivery Systems

On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles

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Dilliard, Sean A., Cheng, Qiang, Siegwart, Daniel J.·2021·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2109256118PMC PMC8719871
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Abstract

Significance: Liver accumulation represents a significant barrier in the development of therapeutically efficacious nanoparticle drug delivery systems. Using a series of lipid nanoparticles with distinct organ-targeting properties, we provide evidence for a plausible mechanism of action for nanoparticle delivery to non-liver tissues. Following intravenous injection, specific proteins in the blood are recruited to the nanoparticle’s surface based on its molecular composition and they endow it with a unique biological identity that governs its ultimate fate in the body. An innovative paradigm emerges from this mechanistic understanding of nanoparticle delivery—endogenous targeting—wherein the molecular composition of a nanoparticle is rationally engineered to interact with specific proteins in the blood to overcome liver accumulation and to target specific organs.

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  • The molecular composition of an LNP modulates the endogenous proteins that bind the nanoparticle and govern its biological fate.

    “Prior studies have demonstrated that the molecular composition of an LNP modulates the endogenous proteins that bind the nanoparticle and govern its biological fate (43).”

    From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [43]

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Research works printed but not linked: 41

  1. [2]Miller J. B., Siegwart D. J., Design of synthetic materials for intracellular delivery of RNAs: From siRNA-mediated gene silencing to CRISPR/Cas gene editing. Nano Res. 11, 5310–5337 (2018). [Google Scholar]
  2. [5]Kowalski P. S., Rudra A., Miao L., Anderson D. G., Delivering the messenger: Advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. [6]Doudna J. A., Charpentier E., Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science 346, 1258096 (2014). [DOI] [PubMed] [Google Scholar]
  4. [8]Wang H. X., et al. , CRISPR/Cas9-based genome editing for disease modeling and therapy: Challenges and opportunities for nonviral delivery. Chem. Rev. 117, 9874–9906 (2017). [DOI] [PubMed] [Google Scholar]
  5. [9]Ventura A., Jacks T., MicroRNAs and cancer: Short RNAs go a long way. Cell 136, 586–591 (2009). [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. [12]Akinc A., et al. , The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 14, 1084–1087 (2019). [DOI] [PubMed] [Google Scholar]
  7. [15]Kose N., et al. , A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection. Sci. Immunol. 4, eaaw6647 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. [16]Wei T., et al. , Delivery of tissue-targeted scalpels: Opportunities and challenges for in vivo CRISPR/Cas-based genome editing. ACS Nano 14, 9243–9262 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. [17]Adams D., et al. , Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018). [DOI] [PubMed] [Google Scholar]
  10. [20]Kulkarni J. A., Cullis P. R., van der Meel R., Lipid nanoparticles enabling gene therapies: From concepts to clinical utility. Nucleic Acid Ther. 28, 146–157 (2018). [DOI] [PubMed] [Google Scholar]
  11. [21]Cheng Q., et al. , Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. [22]Wei T., Cheng Q., Min Y. L., Olson E. N., Siegwart D. J., Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing. Nat. Commun. 11, 3232 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. [23]Lee S. M., et al. , A systematic study of unsaturation in lipid nanoparticles leads to improved mRNA transfection in vivo. Angew. Chem. Int. Ed. Engl. 60, 5848–5853 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. [25]Zhou K., et al. , Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model. Proc. Natl. Acad. Sci. U.S.A. 113, 520–525 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. [26]Cheng X., Lee R. J., The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery. Adv. Drug Deliv. Rev. 99, 129–137 (2016). [DOI] [PubMed] [Google Scholar]
  16. [27]Zhang Y.-N., Poon W., Tavares A. J., McGilvray I. D., Chan W. C. W., Nanoparticle-liver interactions: Cellular uptake and hepatobiliary elimination. J. Control. Release 240, 332–348 (2016). [DOI] [PubMed] [Google Scholar]
  17. [29]Monopoli M. P., Aberg C., Salvati A., Dawson K. A., Biomolecular coronas provide the biological identity of nanosized materials. Nat. Nanotechnol. 7, 779–786 (2012). [DOI] [PubMed] [Google Scholar]
  18. [30]Jayaraman M., et al. , Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed. Engl. 51, 8529–8533 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. [31]Mui B. L., et al. , Influence of polyethylene glycol lipid desorption rates on pharmacokinetics and pharmacodynamics of siRNA lipid nanoparticles. Mol. Ther. Nucleic Acids 2, e139 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. [32]Wilson S. C., et al. , Real time measurement of PEG shedding from lipid nanoparticles in serum via NMR spectroscopy. Mol. Pharm. 12, 386–392 (2015). [DOI] [PubMed] [Google Scholar]
  21. [33]Docter D., et al. , Quantitative profiling of the protein coronas that form around nanoparticles. Nat. Protoc. 9, 2030–2044 (2014). [DOI] [PubMed] [Google Scholar]
  22. [34]Ban Z., et al. , Machine learning predicts the functional composition of the protein corona and the cellular recognition of nanoparticles. Proc. Natl. Acad. Sci. U.S.A. 117, 10492–10499 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. [35]Artimo P., et al. , ExPASy: SIB bioinformatics resource portal. Nucleic Acids Res. 40, W597–W603 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. [36]Lara S., et al. , Identification of receptor binding to the biomolecular corona of nanoparticles. ACS Nano 11, 1884–1893 (2017). [DOI] [PubMed] [Google Scholar]
  25. [37]Thiagarajan P., Le A., Benedict C. R., β(2)-glycoprotein I promotes the binding of anionic phospholipid vesicles by macrophages. Arterioscler. Thromb. Vasc. Biol. 19, 2807–2811 (1999). [DOI] [PubMed] [Google Scholar]
  26. [38]Mahley R. W., Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science 240, 622–630 (1988). [DOI] [PubMed] [Google Scholar]
  27. [39]Amici A., et al. , In vivo protein corona patterns of lipid nanoparticles. RSC Adv. 7, 1137–1145 (2017). [Google Scholar]
  28. [40]Pozzi D., et al. , The biomolecular corona of nanoparticles in circulating biological media. Nanoscale 7, 13958–13966 (2015). [DOI] [PubMed] [Google Scholar]
  29. [41]Palchetti S., et al. , The protein corona of circulating PEGylated liposomes. Biochim. Biophys. Acta 1858, 189–196 (2016). [DOI] [PubMed] [Google Scholar]
  30. [42]Walkey C. D., Chan W. C., Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment. Chem. Soc. Rev. 41, 2780–2799 (2012). [DOI] [PubMed] [Google Scholar]
  31. [43]Zhang Y., Wu J. L. Y., Lazarovits J., Chan W. C. W., An analysis of the binding function and structural organization of the protein corona. J. Am. Chem. Soc. 142, 8827–8836 (2020). [DOI] [PubMed] [Google Scholar]
  32. [45]Hammel M., et al. , Mechanism of the interaction of β(2)-glycoprotein I with negatively charged phospholipid membranes. Biochemistry 40, 14173–14181 (2001). [DOI] [PubMed] [Google Scholar]
  33. [46]Caracciolo G., Pozzi D., Capriotti A. L., Cavaliere C., Laganà A., Effect of DOPE and cholesterol on the protein adsorption onto lipid nanoparticles. J. Nanopart. Res. 15, 1498 (2013). [Google Scholar]
  34. [47]Singh B., Fu C., Bhattacharya J., Vascular expression of the alpha(v)beta(3)-integrin in lung and other organs. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L217–L226 (2000). [DOI] [PubMed] [Google Scholar]
  35. [48]Couvelard A., et al. , Expression of integrins during liver organogenesis in humans. Hepatology 27, 839–847 (1998). [DOI] [PubMed] [Google Scholar]
  36. [49]Simpson A., Horton M. A., Expression of the vitronectin receptor during embryonic development: An immunohistological study of the ontogeny of the osteoclast in the rabbit. Br. J. Exp. Pathol. 70, 257–265 (1989). [PMC free article] [PubMed] [Google Scholar]
  37. [50]Dinkla S., et al. , Phosphatidylserine exposure on stored red blood cells as a parameter for donor-dependent variation in product quality. Blood Transfus. 12, 204–209 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. [52]Schöttler S., et al. , Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. Nat. Nanotechnol. 11, 372–377 (2016). [DOI] [PubMed] [Google Scholar]
  39. [53]Kowal R. C., et al. , Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein. J. Biol. Chem. 265, 10771–10779 (1990). [PubMed] [Google Scholar]
  40. [54]Zhang R., et al. , Helper lipid structure influences protein adsorption and delivery of lipid nanoparticles to spleen and liver. Biomater. Sci. 9, 1449–1463 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. [55]Parhiz H., et al. , PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake. J. Control. Release 291, 106–115 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]

Cited by

Sorted by citations

Authors
Dilliard, S. A., Cheng, Q., & Siegwart, D. J.
Affiliations
Harold C. Simmons Comprehensive Cancer Center (US)
Corresponding author
  • Cheng, Qiang
  • Siegwart, Daniel J.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2021-12-21
Volume
118
Issue
52
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2109256118
PMC
PMC8719871
OpenAlex
W4200561001
Cited by
1,018
References
14
Citations by year
2026: 254 · 2025: 287 · 2024: 243 · 2023: 168 · 2022: 65
FWCI
31.07
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 182 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cystic Fibrosis Foundation (SIEGWA18XX0)
  • HHS | NIH | National Institute of Biomedical Imaging and Bioengineering (R01 EB025192-01A1)
  • Cancer Prevention and Research Institute of Texas (RP190251)
  • American Cancer Society (RSG-17-012-01)
  • HHS | NIH | National Cancer Institute (P30 CA142543)
  • HHS | NIH | National Institute of General Medical Sciences (GM007062, GM109776)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
lipid nanoparticles, plasma protein binding, receptor binding, liver-targeted drug delivery
MeSH terms
Gene Editing, Nanoparticle Drug Delivery System, Animals, Humans, Liposomes, Liver, Mice, Inbred C57BL, RNA, Messenger, Tissue Distribution, Mice, Nanoparticles

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