Manganese-coordinated mRNA vaccines with enhanced mRNA expression and immunogenicity induce robust immune responses against SARS-CoV-2 variants

Abstract

It is urgent to develop more effective mRNA vaccines against the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants owing to the immune escape. Here, we constructed a novel mRNA delivery system [IC8/Mn lipid nanoparticles (IC8/Mn LNPs)]with high immunogenicity, via introducing a stimulator of interferon genes (STING) agonist [manganese (Mn)] based on a newly synthesized ionizable lipid (IC8). It was found that Mn can not only promote maturation of antigen-presenting cells via activating STING pathway but also improve mRNA expression by facilitating lysosomal escape for the first time. Subsequently, IC8/Mn LNPs loaded with mRNA encoding the Spike protein of SARS-CoV-2 Delta or Omicron variant (IC8/Mn@D or IC8/Mn@O) were prepared. Both mRNA vaccines induced substantial specific immunoglobulin G responses against Delta or Omicron. IC8/Mn@D displayed strong pseudovirus neutralization ability, T helper 1–biased immune responses, and good safety. It can be concluded that IC8/Mn LNPs have great potential for developing Mn-coordinated mRNA vaccines with robust immunogenicity and good safety.

Lipid‐based nanoparticles as drug delivery systems for cancer immunotherapy

“…The exploration of LNPs, which carry double‐stranded siRNA for the purpose of knocking down checkpoint inhibitors such as anti‐PD‐L1, indoleamine 2,3‐dioxygenase 1 (IDO), and transcription factor forkhead box P3 (FOXP3), among others, is being investigated for the treatment of cancer, as well as for in vitro engineered DC vaccines 111 . Moreover, the utilization of LNPs for the codelivery of antigen‐encoding‐ and immunomodulatory‐encoding‐mRNA has demonstrated the ability to activate innate immunity through the binding of PRRs expressed by APCs 112‐114 . Additionally, the codelivery of immunomodulatory‐encoding mRNA with siRNA for checkpoint inhibitors was shown to counteract the immunosuppressive TME and achieve potent antitumor efficacy 115,116 .…”

Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery

“…[11] To avoid these cationrelated side effects, non-electrostatic loading strategies driven by other interactions like base complementary pairing, [84][85][86] hydrogen bonding, [87] and coordination have been explored for mRNA delivery. [88,89] For example, forming metal/mRNA complex via metal coordination-mediated self-assembly is a practical strategy to condense mRNA. Zou et al applied Zn 2+ -directed mRNA selfassembly to prepare spherical NPs, which preserved the biological function of mRNA and achieved effective green fluorescent protein (GFP) expression, demonstrating the potential of metal coordination-driven mRNA self-assembly and broaden the application of mRNA-based therapeutics.…”

“…[170] In addition to inorganic NPs-based hybrid delivery vehicles, other organic-inorganic hybrid vectors also have been employed for mRNA delivery, such as GO-PEI complexes, metalorganic frameworks (MOFs), and metal ion-containing hybrid vector. [56,89,171] Choi et al presented a GO-PEI hybrid vector to deliver mRNA encoding reprogramming transcription factors, in which positively charged PEI can complex mRNA and negatively charged GO can decrease the toxicity of PEI and protect mRNA from degradation. [56] Sun et al developed a dendritic cationic polymer PGMA(EA)-modified zirconium (Zr)based MOF catiomer for mRNA delivery, which improved the stability of mRNA assemblies and enhanced mRNA transfection efficacy compared to linear catiomer.…”

“…[171] In an example of metal ion-containing hybrid vector, Fan et al prepared an LNP/mRNA formulation containing manganese (Mn) (LNP/Mn@mRNA) by microfluidic mixing method, validating that Mn could facilitate APC maturation by activating the stimulator of interferon genes (STING) pathway and enhance mRNA delivery by promoting lysosomal escape. [89] Biological-chemical hybrid vectors can combine the advantages of biological carriers in terms of biocompatibility and targeting specificity and the advantages of chemical vectors in terms of precise synthesis and stable storage properties. [66] One hybridization strategy is to prepare synthetic NP cores for encapsulating mRNA cargos and then coat the NP cores with biological membranes sourced from cells or bacteria.…”

The clinical progress and challenges of mRNA vaccines

“…It has been shown that LNPs with intrinsic STING activation function induce APC maturation, cytokine expression, and enhanced anti-tumor efficacy (L. Miao et al, 2020). Meanwhile, Fan et al (2022) reported a novel mRNA delivery system (IC8/Mn LNPs) containing a STING agonist (manganese [Mn]), which not only promotes the maturation of APCs by activating the STING pathway, but also improves lysosomal escape to increase mRNA expression. Co-administration of mRNA vaccines and their corresponding adjuvants can significantly enhance the body's immune response to antigens and improve the vaccines' effectiveness (Zhuang et al, 2022).…”