Manipulating the delivery and immunogenicity of DNA vaccines through the addition of CB[8] to cationic polymers
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Challenges with vaccine reactogenicity, stability and access have highlighted the need to develop alternative strategies for formulation and delivery. We explored the incorporation of cucurbit[n]urils (CBs), as supramolecular “hosts”, into nucleic acid-polymer polyplexes. CBs are small, non-toxic, barrel-shaped molecules that transiently crosslink polymers containing supramolecular “guests”, thereby increasing molecular weight (MW) of the complex, a correlate of transfection efficiency. We tested whether the supramolecular interactions of CB[8] impact polyplex function. We generated a library of different CB[8] polyplexes using pDNA, varying N/P (the ratio of polymer to plasmid), the length and guest (phenylalanine, Phe) group frequency of the Polyethylenimine (PEI) polymer backbone. We found that N/P 32 and the 20Phe1 (20kDa PEI with 1 mol% Phe) gave optimal gene expression and that incorporating CB[8] in polyplex formulations improved gene expression, both in vitro and in vivo. Despite increases in gene expression, inclusion of CB[8] in formulations with higher guest-binding capacity led to decreased immunogenicity, possibly as a result of dampened innate immune responses. Our data show that CB[8] polyplexes increase gene delivery and expression but alter inflammatory responses. These findings highlight that rational design of the CB[8] polymer system can enable nucleic acid delivery for both vaccine and therapeutic applications.
Date Issued
2025-09-09
Date Acceptance
2025-06-02
Citation
Molecular Therapy: Nucleic Acids, 2025, 36 (3)
ISSN
2162-2531
Publisher
Elsevier
Journal / Book Title
Molecular Therapy: Nucleic Acids
Volume
36
Issue
3
Copyright Statement
© 2025 The Authors. Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Publication Status
Published
Article Number
102585
Date Publish Online
2025-06-30