Lipid-based mRNA vaccine delivery systems

Abstract

Synthetic mRNAs can become biopharmaceutics allowing vaccination against cancer, bacterial and virus infections. Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Although immune responses are generated by naked mRNAs, their formulations with chemical carriers are expected to provide more specificity and internalization in dendritic cells (DCs) for better immune responses and dose reduction. This review reports lipid-based formulations (LBFs) that have proved preclinical efficacy. The selective delivery of mRNA LBFs to favor intracellular accumulation in DCs and reduction of the effective doses is discussed, notably to decorate LBFs with carbohydrates or glycomimetics allowing endocytosis in DCs. We also report how smart intracellular delivery is achieved using pH-sensitive lipids or polymers for an efficient mRNA escape from endosomes and limitations regarding cytosolic mRNA location for translation.

Keywords:

• dendritic cells
• glycomimetics
• glycotargeting
• histidine
• lipid-based formulations
• lipoplexes
• lipopolyplexes
• mannose receptors
• pH-sensitive delivery
• RNA vaccines

Financial & competing interests disclosure

The works of P Midoux and C Pichon were supported in part by grants from: Ligue contre le Cancer, EU FP7 (Project FP7-HEALTH-2013_INNOVATION-1, UniVax Project n° 601738) and ARD 2020 Biomédicaments (Région Centre, France). The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Cancer clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of specific and relevant immune responses.

• It is desirable to develop smart delivery systems suitable to protect synthetic mRNA from RNAse degradation and help it to penetrate in dendritic cells (DCs) to improve vaccination and reduce mRNA doses.

• Lipoplexes, lipopolyplexes, lipid nanoparticles and lipid emulsions are suitable lipid-based formulations (LBFs) for mRNA delivery. Some of them have proved preclinical efficacy but till now clinical efficacy is missing.

• When LBFs are internalized in DCs by clathrin- or caveolae-dependent endocytosis, the escape of mRNA from acidic vesicles (endosomes) can be promoted by using pH-sensitive lipids and polymers that induce membrane fusion and proton sponge effect in mildly acidic medium, respectively.

• It is not yet known whether mRNA is delivered in the cytosol free or associated with LBFs. No data are yet reported on the intracellular trafficking, location and cytosolic mobility allowing synthetic mRNAs to reach ribosomes for translation.

• The selective delivery of mRNA vaccines to DCs favoring its intracellular accumulation aims at reducing the effective dose. DC-targeting can be achieved by decoration of LBFs with selective ligands recognized by surface receptors of DCs allowing endocytosis. For this purpose, glycotargeting with carbohydrates or glycomimetics recognized by sugar receptors expressed by DCs notably the mannose and DC-SIGN receptors is a good strategy to enhance antigen uptake, presentation and immune response.

Notes