Protein and mRNA Delivery Enabled by Cholesteryl‐Based Biodegradable Lipidoid Nanoparticles
Abstract
Developing safe and efficient delivery systems for therapeutic biomacromolecules is a long‐standing challenge. Herein, we report a newly developed combinatorial library of cholesteryl‐based disulfide bond‐containing biodegradable cationic lipidoid nanoparticles. We have identified a subset of this library which is effective for protein and mRNA delivery in vitro and in vivo. These lipidoids showed comparable transfection efficacies but much lower cytotoxicities compared to the Lpf2k in vitro. In vivo studies in adult mice demonstrated the successful delivery of genome engineering protein and mRNA molecules in the skeletal muscle (via intramuscular injection), lung and spleen (via intravenous injection), and brain (via lateral ventricle infusion).
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Cas9 mRNA has not been tested using LNPs in the brain yet.
“Notably, there has been an effort of Cas9 mRNA/sgRNA delivery using LNPs in cultured cells by Li et al. (2020), however, Cas9 mRNA has not been tested using LNPs in the brain yet (7).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [7]
The Results and Discussion report Cas9 mRNA/sgRNA delivery with LNPs in cultured GFP-HEK cells, while the brain experiments used Cre mRNA/LNPs. This supports the distinction between the paper’s cell and brain tests, but it does not establish the broader claim that Cas9 mRNA had not been tested with LNPs in the brain by anyone. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAfter ICV LNP mRNA delivery, transfected cells appeared localized to restricted brain regions, primarily the cells lining the ventricle wall, with small levels of transfection in brain tissue.
“However, transfected cells appeared to be localized to the restricted brain regions, primarily to the cells lining the ventricle wall, with small levels of transfection in the brain tissue.”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [7]
The Results and Discussion report that lateral-ventricle infusion of Cre mRNA/LNPs transfected cells lining the ventricle and cells in the hippocampus, with hippocampal signals concentrated in specific regions. The paper does not establish that transfection occurred primarily at the ventricle wall or quantify the level in brain tissue as small; it says overall transfection efficacy remains to be determined. Page numbers are not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredmRNA can be delivered using LNPs after ICV injection into mouse brain tissue.
“Further studies by Tanaka et al. (2018) and Li et al. (2020) demonstrated that mRNA can also be delivered using LNPs after ICV injection into mouse brain tissue (6, 7).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [7]
The Results and Discussion report that Cre mRNA-loaded LNPs delivered mRNA to cells in adult mouse brains via the lateral ventricle. However, the paper used continuous infusion through a cannula over several days, not an ICV injection, so it does not establish the claim for that administration method. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLNP mRNA complexes have excellent biocompatibility and can transfect a variety of tissues and organs.
“LNP mRNA complexes have excellent biocompatibility and can transfect a variety of tissues and organs (5–9).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [7]
The Results and Discussion report negligible cytotoxicity for mRNA-loaded OCholB LNPs in HeLa cells and functional mRNA delivery in mouse skeletal muscle, spleen, and brain tissue (page unavailable). The claim is broader than these findings: it describes LNP–mRNA complexes generally as having excellent biocompatibility, whereas the paper's toxicity evidence for loaded complexes is in vitro and it cautions that cargo may change in vivo toxicity. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe concentrations of LNP mRNA complexes used were significantly lower than previously reported doses used for ICV injections while the transfected brain regions were significantly larger than that observed with an ICV injection (7).
“Notably, the concentration of LNP mRNA complexes that we used in our study were significantly lower than the previously reported doses used for ICV injections while the transfected brain regions were significantly larger than that observed with an ICV injection (7).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [7]
The Results and Discussion (page unavailable) describe Cre mRNA/LNP infusion into the lateral ventricle of mice and report transfected cells along the ventricle and in the hippocampus. This supports citing the paper as a prior ventricular-delivery study with a reported transfection pattern. Our copy does not give a ventricular-infusion dose or establish the citing study’s lower-dose and larger-region comparisons. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Li et al. (2020) infused LNPs containing Cre mRNA into the lateral ventricle of adult Ai14 mice continuously from day 1 to day 4 using an osmotic pump connected to a brain cannula, resulting in tdTomato expression in cells lining the injected lateral ventricle and in the hippocampus.
“More recently, Li et al. (2020) infused their LNPs, which contained Cre mRNA, into the lateral ventricle of adult Ai14 mice continuously from day 1 to day 4 using an osmotic pump connected to a brain cannula. As a result of Cre recombination, tdTomato expression was observed in the cells lining the injected lateral ventricle (hypothesized to be ependymal cells) and in the hippocampus, specifically”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [7]
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Khare, P., Edgecomb, S. X., Hamadani, C. M., Tanner, E. E. L., & S Manickam, D. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114861 · Cited by 187 · see citing works
Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection
Tuma, J., Chen, Y.-J., Collins, M. G., Paul, A., Li, J., Han, H., Sharma, R., Murthy, N., & Lee, H. Y. (2023) · Biochemistry · doi:10.1021/acs.biochem.3c00371 · Cited by 65 · see citing works
- Authors
- Li, Y., Jarvis, R., Zhu, K., Glass, Z., Ogurlu, R., Gao, P., Li, P., Chen, J., Yu, Y., Yang, Y., & Xu, Q.
- Affiliations
- Tufts University (US)
- Corresponding author
- Xu, Qiaobing
- ORCID
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2020-06-15
- Volume
- 59
- Issue
- 35
- Pages
- 14957-14964
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- PMC
- PMC7679290
- OpenAlex
- W4235510043
- Cited by
- 75
- References
- 8
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 13 · 2023: 11 · 2022: 8 · 2021: 19 · 2020: 4
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- Funders
- National Institutes of Health (R01 EB027170-01, UG3 TR002636-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- protein delivery, mRNA delivery, gene therapy vectors, transfection efficiency, cytotoxicity, intramuscular injection, intravenous injection, intracerebroventricular administration
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