Solid Lipid Nanoparticle Carrier Platform Containing Synthetic TLR4 Agonist Mediates Non-Viral DNA Vaccine Delivery

Abstract

There is a growing demand for better delivery systems to improve the stability and efficacy of DNA vaccines. Here we report the synthesis of a non-viral DNA vaccine delivery system using a novel adjuvanted solid lipid nanoparticle (SLN-A) platform as a carrier for a DNA vaccine candidate encoding the Urease alpha (UreA) antigen from Helicobacter pylori. Cationic SLN-A particles containing monophosphoryl lipid A (adjuvant) were synthesised by a modified solvent-emulsification method and were investigated for their morphology, zeta potential and in vitro transfection capacity. Particles were found to bind plasmid DNA to form lipoplexes, which were characterised by electron microscopy, dynamic light scattering and fluorescence microscopy. Cellular uptake studies confirmed particle uptake within 3 h, and intracellular localisation within endosomal compartments. In vitro studies further confirmed the ability of SLN-A particles to stimulate expression of pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) in human macrophage-like Tohoku Hospital Pediatrics-1 (THP-1) cells. Lipoplexes were found to be biocompatible and could be efficiently transfected in murine immune cells for expression of recombinant H. pylori antigen Urease A, demonstrating their potential as a DNA vaccine delivery system.

DNA Based Vaccine Expressing SARS-CoV-2 Spike-CD40L Fusion Protein Confers Protection Against Challenge in a Syrian Hamster Model

“…One potential avenue for improvement is through the use of alternative immunization devices, such as jet injectors, electroporation and gene-guns, all of which have been shown to improve the uptake of DNA vaccines and their subsequent efficacy relative to needle injection (61,62). Another promising strategy is encapsulating the DNA vaccines in nanoparticles, which can improve DNA uptake, protect DNA from DNase degradation and act as an vaccine adjuvant (63)(64)(65)(66). The successful usage of lipid-nanoparticle formulated RNA vaccines against SARS-CoV-2 lends credence to their use as a DNA vaccine delivery vector (67).…”

Pandemic Preparedness Against Influenza: DNA Vaccine for Rapid Relief

“…DNA vaccines against influenza have been in development since the 1990's with promising data in pre-clinical models, but the reduced efficacy often observed in larger animals and humans has hampered progression to clinical application (17). New formulations such as lipid nanoparticles (32,33), viral vector formulations (34,35), and gene delivery methods (36) have increased vaccine efficacy, and a naked DNA vaccine from Inovio against SARS-CoV-2 just entered Phase 3 clinical testing (37).…”

Multifunctional Immunoadjuvants for Use in Minimalist Nucleic Acid Vaccines

“…MPLA adjuvant formulations can be further optimized to incorporate antigen-encoding nucleic acids. Solid lipid nanoparticles (SLNs), nanosized emulsions containing solid oil cores at room and body temperatures ( Figure 3 ), decorated with MPLA as an adjuvant surfactant and DC cholesterol as a cationic surfactant, were used to adsorb pDNA on the surface to protect pDNA from enzymatic degradation by strong electrostatic attractions [ 78 ]. MPLA incorporated into nucleoside-modified mRNA lipoplexes based on DOTAP/cholesterol helped to restore the immune response to levels comparable to those of unmodified mRNA lipoplexes [ 79 ].…”