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Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery

Nature Nanotechnology (2024)Cite this article

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Abstract

Systemic delivery of messenger RNA (mRNA) for tissue-specific targeting using lipid nanoparticles (LNPs) holds great therapeutic potential. Nevertheless, how the structural characteristics of ionizable lipids (lipidoids) impact their capability to target cells and organs remains unclear. Here we engineered a class of siloxane-based ionizable lipids with varying structures and formulated siloxane-incorporated LNPs (SiLNPs) to control in vivo mRNA delivery to the liver, lung and spleen in mice. The siloxane moieties enhance cellular internalization of mRNA-LNPs and improve their endosomal escape capacity, augmenting their mRNA delivery efficacy. Using organ-specific SiLNPs to deliver gene editing machinery, we achieve robust gene knockout in the liver of wild-type mice and in the lungs of both transgenic GFP and Lewis lung carcinoma (LLC) tumour-bearing mice. Moreover, we showed effective recovery from viral infection-induced lung damage by delivering angiogenic factors with lung-targeted Si5-N14 LNPs. We envision that our SiLNPs will aid in the clinical translation of mRNA therapeutics for next-generation tissue-specific protein replacement therapies, regenerative medicine and gene editing.

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Fig. 1: A combinatorial library of siloxane-incorporated ionizable lipids with tunable structures for tissue-specific mRNA delivery.
Fig. 2: Siloxane moiety incorporation improves cellular internalization and endosomal escape.
Fig. 3: In vivo structure–activity studies of siloxane-incorporated lipidoid formulations for mRNA delivery and organ selectivity to the liver, lungs and spleen.
Fig. 4: Liver-targeted mRNA delivery and CRISPR–Cas9 gene editing by SiLNPs.
Fig. 5: Lung-targeted mRNA delivery and CRISPR–Cas9 gene editing by SiLNPs.
Fig. 6: Lung-targeted SiLNPs for efficient vascular repair.

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Data availability

All relevant data supporting the findings of this study are available within the paper, Supplementary Information or Source Data file. Source data are provided with this paper.

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Acknowledgements

M.J.M. acknowledges support from a US National Institutes of Health (NIH) Director’s New Innovator Award (DP2 TR002776), a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET), a US National Science Foundation CAREER Award (CBET-2145491) and the National Institutes of Health (NICHD R01 HD115877). A.E.V. acknowledges support from NIH grants (R01HL153539) and the Margaret Q. Landenberger Foundation. S.J.S. and K.L.S. are supported by an NSF Graduate Research Fellowship (award 1845298). R.P. was supported by an NIH F30 fellowship (F30HL162465-01A1). Z.X. is supported by a CRI Irvington fellowship (grant number CRI4168) from the Cancer Research Institute. We thank The Wistar Institute, the Pathology Core, Nucleic Acids Technology Core, and Program for Comparative Medicine at the Gene Therapy Program for technical assistance and I. Muthuramu for analysis of deep sequencing data. Elements in Figs. 1, 4, 5 and 6 were created with BioRender.com.

Author information

Author notes

  1. These authors contributed equally: Lulu Xue, Gan Zhao, Ningqiang Gong.

Authors and Affiliations

  1. Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Lulu Xue, Ningqiang Gong, Xuexiang Han, Sarah J. Shepherd, Rohan Palanki, Junchao Xu, Kelsey L. Swingle, Rakan El-Mayta, Il-Chul Yoon, Jingcheng Xu & Michael J. Mitchell

  2. Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Gan Zhao, Zebin Xiao & Andrew E. Vaughan

  3. Yangtze Delta Region Institute (Huzhou), University of Electronic Science and Technology of China, Huzhou, China

    Xinhong Xiong & Jiaxi Cui

  4. Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Claude C. Warzecha, Vivek Chowdhary, Lili Wang & James M. Wilson

  5. Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, China

    Jiaxi Cui

  6. Department of Materials Science and Engineering, University of Delaware, Newark, Delaware, USA

    Yi Shi & Darrin J. Pochan

  7. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Mohamad-Gabriel Alameh & Drew Weissman

  8. Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Mohamad-Gabriel Alameh, Drew Weissman & Michael J. Mitchell

  9. Department of Bioengineering, Temple University, Philadelphia, Pennsylvania, USA

    Karin Wang

  10. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael J. Mitchell

  11. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael J. Mitchell

  12. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael J. Mitchell

  13. Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael J. Mitchell

Authors
  1. Lulu Xue
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Contributions

L.X. and M.J.M. conceived the concept. L.X. and X.X. designed and synthesized all the siloxane-incorporated ionizable lipids used in this study. L.X., N.G., G.Z., X.H., C.C.W., V.C., R.P., R.E.-M. and Y.S. performed the experiments. L.X., N.G., S.J.S., K.L.S., K.W. and M.J.M. wrote the paper. L.X., G.Z., N.G., X.H., S.J.S., X.X., Z.X., R.P., J.X., K.L.S., C.C.W., R.E.-M., V.C., I.-C.Y., J.X., J.C., Y.S., M.-G.A., K.W., L.W., D.J.P., D.W., A.E.V., J.M.W. and M.J.M. reviewed and commented on the paper.

Corresponding author

Correspondence to Michael J. Mitchell.

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Competing interests

L.X. and M.J.M. are inventors on a patent filed by the Trustees of the University of Pennsylvania (International Patent Application No. PCT/US23/66564) describing the lipid nanoparticle technology in this study. J.M.W. is a paid advisor to and holds equity in iECURE, Passage Bio and the Center for Breakthrough Medicines (CBM). He also holds equity in the former G2 Bio asset companies and Ceva Santé Animale. He has sponsored research agreements with Alexion Pharmaceuticals, Amicus Therapeutics, CBM, Ceva Santé Animale, Elaaj Bio, FA212, Foundation for Angelman Syndrome Therapeutics, former G2 Bio asset companies, iECURE and Passage Bio, which are licensees of Penn Technology. J.M.W., L.W. and C.C.W are inventors on patents that have been licensed to various biopharmaceutical companies and for which they may receive payments. D.W. is named on patents that describe the use of nucleoside-modified mRNA as a platform to deliver therapeutic proteins and vaccines. M.J.M., D.W. and M.-G.A. are also named on patents describing the use of lipid nanoparticles and lipid compositions for nucleic acid delivery. The other authors declare no competing interests.

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Nature Nanotechnology thanks Yusuke Sato and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Formulation parameters and characterization of SiLNPs.

a, SiLNPs formulation parameters. Siloxane-incorporated lipidoids, DOPE, cholesterol, and C14PEG2K with molar ratio of 35%, 16%, 46.5%, and 2.5% were used for SiLNPs formulation. b, Representative cryogenic transmission electron microscopy (cryo-TEM) image of SiLNP morphology. Scale bar: 100 nm. c, Hydrodynamic size distribution of representative SiLNP.

Source data

Extended Data Fig. 2 Blood chemistry evaluation of mice after administration of Si6-C14b LNP co-delivering Cas9 mRNA and TTR sgRNA.

(a) AST, (b) ALT, (c) BUN, and (d) Creatinine levels of blood samples obtained from mice treated with PBS and Si6-C14b LNP (RNA dose: 3 mg kg−1). Data are presented as mean ± s.e.m. (n = 3 mice for PBS treated groups; n =4 for LNP treated groups).

Source data

Supplementary information

Supplementary Information

Supplementary Text, Tables 1–9, Schemes 1–5 and Figs. 1–51.

Reporting Summary

Supplementary Data 1

Statistical source data for the supplementary figures.

Source data

Source Data Fig. 1

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Source Data Fig. 2

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Source Data Fig. 3

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Source Data Fig. 4

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Source Data Fig. 5

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Source Data Fig. 6

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Source Data Extended Data Fig./Table 1

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Source Data Extended Data Fig./Table 2

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Xue, L., Zhao, G., Gong, N. et al. Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01747-6

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