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Cited by 33RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryDendrimers and Hyperbranched Polymers

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Preparation of Messenger RNA Nanomicelles via Non-Cytotoxic PEG-Polyamine Nanocomplex for Intracerebroventicular Delivery: A Proof-of-Concept Study in Mouse Models

Open access
Chan, Long Yi, Khung, Yit Lung, Lin, Chin-Yu·2019·Nanomaterials
DOI 10.3390/nano9010067PMC PMC6359661
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Abstract

The specific delivery of messenger RNA (mRNA) is an excellent alternative to plasmid DNA, due to the latter’s potential risk for random integration into the host genome. In this study, we propose the use of specially tailored polyplex nanomicelles for the intravenous delivery of mRNA into the brain of mice. In brief, along the backbone of a polyaspartamide polymer that is terminated with a 42k Polyethylene glycol chain (PEG), aminoethylene-repeating groups (two, three, and four units, respectively) were conjugated to side-chains to promote electrostatic interactions with mRNA. This structural configuration would ultimately condense into a polyplex nanomicelle ranging between 24 and 34 nm, as was confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS) while the chemistry of the synthesis was validated through NMR analysis. Subsequently, we hypothesized an important correlation pertaining to the role of hydrogen bonding between the interaction of polyamine and mRNA in due course. As a proof of concept, we encapsulated the luciferase (Luc2) mRNA as a reporter gene through in vitro transcription (IVT) and subsequently infused the polyplex nanomicelles into mouse brains via an intracerebroventricular (ICV) injection to bypass the blood–brain barriers (BBB). Data revealed that PEGylated polyplex nanomicelles possessing four repeating units of aminoethylene groups had exhibited the best Luc2 mRNA delivery efficiency with no significant immune response registered.

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Figure 1 (a) Graphical illustration on the assembly of the polyamine of various length (DET, TET, and TEP) respective via the aminolysis of the benzylic alcohol side chains and (b) the subsequent condensation with mRNA into nanomicelles in physiological environment.
Figure 1 (a) Graphical illustration on the assembly of the polyamine of various length (DET, TET, and TEP) respective via the aminolysis of the benzylic alcohol side chains and (b) the subsequent condensation with mRNA into nanomicelles in physiological environment.CC BY · PubMed Central
Figure 2 Due to the nature of the nucleophilic substitution of the benzylic alcohol, we postulated the range of different reaction sites on the polyamine as exemplified by the reaction of TEP, resulting in possible differences in extension of arms.
Figure 2 Due to the nature of the nucleophilic substitution of the benzylic alcohol, we postulated the range of different reaction sites on the polyamine as exemplified by the reaction of TEP, resulting in possible differences in extension of arms.CC BY · PubMed Central
Figure 3 TEM and DLS analysis of Lux-2 mRNA condensed nanomicelle of (a) PEG-PAsp(DET), (b) PEG-PAsp(TET) and (c) PEG-PAsp(TEP) with the white bar representing 200 nm. Both DET and TEP were found to be marginally larger (31–35 nm) compared to TET (~24 nm), and this has been attributed to the uneven extension of chain arm upon aminolysis.
Figure 3 TEM and DLS analysis of Lux-2 mRNA condensed nanomicelle of (a) PEG-PAsp(DET), (b) PEG-PAsp(TET) and (c) PEG-PAsp(TEP) with the white bar representing 200 nm. Both DET and TEP were found to be marginally larger (31–35 nm) compared to TET (~24 nm), and this has been attributed to the uneven extension of chain arm upon aminolysis.CC BY · PubMed Central
Figure 4 Hydrogen bonding of TET via (a) tail group amine and (b) secondary amine resulting in “uneven” chain arms.
Figure 4 Hydrogen bonding of TET via (a) tail group amine and (b) secondary amine resulting in “uneven” chain arms.CC BY · PubMed Central
Figure 5 The ICV infusion of trypan blue to demonstrate the mixture solution would flow to whole brain via the connected brain ventricles. (a) Illustration of infusion site. (b) Intracerebroventricular infusion through micro-syringe. (c) Trypan blue flow to whole brain via the connected ventricles.
Figure 5 The ICV infusion of trypan blue to demonstrate the mixture solution would flow to whole brain via the connected brain ventricles. (a) Illustration of infusion site. (b) Intracerebroventricular infusion through micro-syringe. (c) Trypan blue flow to whole brain via the connected ventricles.CC BY · PubMed Central
Figure 6 (a) IVIS analysis after Luc2 mRNA polyplex nanomicelles ICV-infusion over a course of 72 h to evaluate the efficacy of signal retention in the brain. (b) Total luminescence analysis at 4–72 h post-infusion.
Figure 6 (a) IVIS analysis after Luc2 mRNA polyplex nanomicelles ICV-infusion over a course of 72 h to evaluate the efficacy of signal retention in the brain. (b) Total luminescence analysis at 4–72 h post-infusion.CC BY · PubMed Central

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Metadata

Authors
Chan, L. Y., Khung, Y. L., & Lin, C.-Y.
Affiliations
China Medical University (TW)
Corresponding author
  • Khung, Yit Lung
  • Lin, Chin-Yu
ORCID
Venue
Nanomaterials
Publisher
MDPI AG
Published
2019-01-05
Volume
9
Issue
1
Pages
67
ISSN
2079-4991 (ISSN-L)
DOI
10.3390/nano9010067
PMC
PMC6359661
OpenAlex
W2908235105
Cited by
33
References
29
Citations by year
2026: 1 · 2025: 7 · 2024: 3 · 2023: 7 · 2022: 8 · 2021: 5 · 2020: 2
FWCI
1.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Nanomaterials (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Ministry of Science and Technology, Taiwan (107-2314-B-039-023, 107-2622-E-039-003, 107-2113-M-039-002-MY2)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
Keywords
polyaspartamide, intracerebroventricular administration, blood-brain barrier bypass, mRNA delivery, luciferase reporter, hydrogen bonding, immune response

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