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Review
. 2025 Mar 1;15(3):359.
doi: 10.3390/biom15030359.

Revolutionizing mRNA Vaccines Through Innovative Formulation and Delivery Strategies

Munazza Fatima  1   2 , Timothy An  2 , Kee-Jong Hong  1   2   3   4
Affiliations
Review

Revolutionizing mRNA Vaccines Through Innovative Formulation and Delivery Strategies

Munazza Fatima et al. Biomolecules. .

Abstract

Modernization of existing methods for the delivery of mRNA is vital in advanced therapeutics. Traditionally, mRNA has faced obstacles of poor stability due to enzymatic degradation. This work examines cutting-edge formulation and emerging techniques for safer delivery of mRNA vaccines. Inspired by the success of lipid nanoparticles (LNP) in delivering mRNA vaccines for COVID-19, a variety of other formulations have been developed to deliver mRNA vaccines for diverse infections. The meritorious features of nanoparticle-based mRNA delivery strategies, including LNP, polymeric, dendrimers, polysaccharide-based, peptide-derived, carbon and metal-based, DNA nanostructures, hybrid, and extracellular vesicles, have been examined. The impact of these delivery platforms on mRNA vaccine delivery efficacy, protection from enzymatic degradation, cellular uptake, controlled release, and immunogenicity has been discussed in detail. Even with significant developments, there are certain limitations to overcome, including toxicity concerns, limited information about immune pathways, the need to maintain a cold chain, and the necessity of optimizing administration methods. Continuous innovation is essential for improving delivery systems for mRNA vaccines. Future research directions have been proposed to address the existing challenges in mRNA delivery and to expand their potential prophylactic and therapeutic application.

Keywords: DNA nanostructures; dendrimer; extracellular vesicles; hybrid nanoparticles; lipid nanoparticles; liposomes; mRNA delivery; polymeric nanoparticles.

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Conflict of interest statement

We declare no conflicts of interest concerning the publication.

Figures

Figure 1
Figure 1
(a) Models of LNP and (b) Structures of LNP components adopted from [37].
Figure 2
Figure 2
The chemical structure of fluorine modified ionizable lipid (F-L319) adopted from [38].
Figure 3
Figure 3
Adjuvant lipidoid-substituted SARS-CoV-2 mRNA-LNP vaccine and its mechanism of elicit immunity adopted from [39]. After injection, mRNA translated inside DCs, antigen is processed and presented, inducing adaptive immune responses.
Figure 4
Figure 4
Targeted delivery of LNPs assisted mRNA vaccines adopted from [41].
Figure 5
Figure 5
Structure of polymeric nanoparticles and dendrimer adopted from [59].
Figure 6
Figure 6
Schematic representation of dendrimer (a) dendrimer showing G0, G1, G2, and G3 generations and (b) amphiphilic dendrimers, red and blue colors representing hydrophobic and hydrophilic portions, respectively, adopted from [63].
Figure 7
Figure 7
Structure of lipid peptide nanocomplex for mRNA vaccine delivery [97].
Figure 8
Figure 8
Surface chemistry of CNT for mRNA delivery adopted from [105].
Figure 9
Figure 9
(a) Schematic diagram for the synthesis of mRNA-MPN NPs through metal–phenolic-mediated assembly of PEG, mRNA, phenolic ligands, and metal ions, (b) transfection efficiency of mRNA-MPN NPs assembled with various metal ions, and (c) mRNA expression in harvested organs using MPN NPs with different ZrIV-to-EGCG mass ratios adopted from [108]. Analysis was carried out using one-way ANOVA or one-way ANOVA with Tukey’s multiple comparisons test. In liver (** p  =  0.0066), kidney (**** p  =  5.1 × 10−5, ** p  =  0.0078), and brain (** p  =  0.0078).
Figure 10
Figure 10
(a) Schematic representation of DNA nanohydrogel-assisted mRNA delivery and its intracellular pH-responsive release, (b) fluorescence intensity analysis of Xtail + Itail and Xcap + Icap under different pH conditions, and (c) switch cycles of the Xtail + Itail and Xcap + Icap between a of pH 5.0 and 8.0, adopted from [113].
Figure 11
Figure 11
Molecular design and preparation of the nanomachine for mRNA delivery. (a) The monomers and their corresponding legends used in the polymerization for the preparation of DNA-integrated nanoparticles (DNA-NPs) and (b) the synthesis and thermal-responsive phase transition of PNIPAM-based nanostructure adopted from [115].
Figure 12
Figure 12
(a) Composition tuning of DOPE/DOTMA, (b,c) chemical structures of DOPE and DOTMA, (d) composition dependent zeta potential, and (e) corresponding relative fluorescence intensity adopted from [120].
Figure 13
Figure 13
Molecular structure and composition of extracellular vesicles derived from mammalian cells (a) and gram-negative bacteria (b) adopted from [131].
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