Dataset Information

Lipid-Polymer Hybrid "Particle-in-Particle" Nanostructure Gene Delivery Platform Explored for Lyophilizable DNA and mRNA COVID-19 Vaccines.

ABSTRACT: SARS-CoV-2 has led to a worldwide pandemic, catastrophically impacting public health and the global economy. Herein, a new class of lipid-modified polymer poly (β-amino esters) (L-PBAEs) is developed via enzyme-catalyzed esterification and further formulation of the L-PBAEs with poly(d,l-lactide-coglycolide)-b-poly(ethylene glycol) (PLGA-PEG) leads to self-assembly into a "particle-in-particle" (PNP) nanostructure for gene delivery. Out of 24 PNP candidates, the top-performing PNP/C12-PBAE nanoparticles efficiently deliver both DNA and mRNA in vitro and in vivo, presenting enhanced transfection efficacy, sustained gene release behavior, and excellent stability for at least 12 months of storage at -20 °C after lyophilization without loss of transfection efficacy. Encapsulated with spike encoded plasmid DNA and mRNA, the lipid-modified polymeric PNP COVID-19 vaccines successfully elicit spike-specific antibodies and Th1-biased T cell immune responses in immunized mice even after 12 months of lyophilized storage at -20 °C. This newly developed lipid-polymer hybrid PNP nanoparticle system demonstrates a new strategy for both plasmid DNA and mRNA delivery with the capability of long-term lyophilized storage.

SUBMITTER: Li Z

PROVIDER: S-EPMC9349454 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Lipid-Polymer Hybrid "Particle-in-Particle" Nanostructure Gene Delivery Platform Explored for Lyophilizable DNA and mRNA COVID-19 Vaccines.

Li Zhongyu Z Zhang Xue-Qing XQ Ho William W Bai Xin X Jaijyan Dabbu Kumar DK Li Fengqiao F Kumar Ranjeet R Kolloli Afsal A Subbian Selvakumar S Zhu Hua H Xu Xiaoyang X

Advanced functional materials 20220722 40

SARS-CoV-2 has led to a worldwide pandemic, catastrophically impacting public health and the global economy. Herein, a new class of lipid-modified polymer poly (β-amino esters) (L-PBAEs) is developed via enzyme-catalyzed esterification and further formulation of the L-PBAEs with poly(d,l-lactide-coglycolide)-<i>b</i>-poly(ethylene glycol) (PLGA-PEG) leads to self-assembly into a "particle-in-particle" (PNP) nanostructure for gene delivery. Out of 24 PNP candidates, the top-performing PNP/C12-PBA ...[more]

PMID: 35942271

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Project description:To combine the excellent transfection properties of lipids with the high stability of polymeric nanoparticles, we designed a hybrid system with a polymeric core surrounded by a shell of different lipids. The aim is to use this technology for skin vaccination purposes where the transfection of dendritic cells is crucial. Based on a carrier made of PLGA and the positively charged lipid DOTMA, we prepared a panel of nanocarriers with increasing amounts of the zwitterionic phospholipid DOPE in the lipid layer to improve their cell tolerability. We selected a nomenclature accordingly with numbers in brackets to represent the used mol% of DOPE and DOTMA in the lipid layer, respectively. We loaded mRNA onto the surface and assessed the mRNA binding efficacy and the degree of protection against RNases. We investigated the influence of the lipid composition on the toxicity, uptake and transfection in the dendritic cell line DC 2.4 challenging the formulations with different medium supplements like fetal calf serum (FCS) and salts. After selecting the most promising candidate, we performed an immune stimulation assay with primary mouse derived dendritic cells. The experiments showed that all tested lipid-polymer nanoparticles (LPNs) have comparable hydrodynamic parameters with sizes between 200 and 250 nm and are able to bind mRNA electrostatically due to their positive zetapotential (20-40 mV for most formulations). The more of DOPE we add, the more free mRNA we find and the better the cellular uptake reaching approx. 100% for LPN(60/40)-LPN(90/10). This applies for all tested formulations leading to LPN(70/30) with the best performance, in terms of 67% of live cells with protein expression. In that case, the supplements of the medium did not influence the transfection efficacy (56% vs. 67% (suppl. medium) for live cells and 63% vs. 71% in total population). We finally confirmed this finding using mouse derived primary immune cells. We can conclude that a certain amount of DOTMA in the lipid coating of the polymer core is essential for complexation of the mRNA, but the zwitterionic phospholipid DOPE is also important for the particles' performance in supplemented media.

Dataset Information

Lipid-Polymer Hybrid "Particle-in-Particle" Nanostructure Gene Delivery Platform Explored for Lyophilizable DNA and mRNA COVID-19 Vaccines.

Publications

Lipid-Polymer Hybrid "Particle-in-Particle" Nanostructure Gene Delivery Platform Explored for Lyophilizable DNA and mRNA COVID-19 Vaccines.

Similar Datasets

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