Recent Advances in Lipid Nanoparticles and Their Safety Concerns for mRNA Delivery

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  Figure 8. (a) Adjuvant lipidoid-substituted LNPs augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Reproduced from ref. [36]. Copyright Nature Publishing Group. (b) The role of nanoparticle format and route of administration on self-amplifying mRNA vaccine potency. Reproduced from ref. [75]. Copyright Elsevier.

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  Figure 1. Lipid nanoparticles for organ-targeting mRNA delivery and their safety concerns for mRNA delivery. (Figure created with BioRender.com).

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  Figure 2. (a) Preparation of SORT LNPs using multiple technical methods for tissue-specific mRNA delivery. Reproduced from ref. [29]. Copyright Nature Publishing Group. (b) In vivo editing of lung stem cells for durable gene correction in mice. Reproduced from ref. [30]. Copyright AAAS. (c) Spleen SORT LNP-generated in situ CAR T cells extend survival in a mouse model of lymphoreplete B cell lymphoma. Reproduced from ref. [31]. Copyright Wiley-VCH. (d) Expanding RNAi to kidneys, lungs, and spleen via SORT siRNA LNPs. Reproduced from ref. [28]. Copyright Wiley-VCH. (e) LNP-mediated drug delivery to the brain. Reproduced from ref. [40]. Copyright Elsevier. (f) Bone-marrow-homing LNPs for genome editing in diseased and malignant hematopoietic stem cells. Reproduced from ref. [26]. Copyright Nature Publishing Group.

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  Figure 3. (a) Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy. Illustration of triple loading of FAK siRNA, Cas9 mRNA, and sgRNA into 5A2-SC8 LNPs. (b) Dendrimer LNPs encapsulating FAK siRNA, Cas9 mRNA, and targeted sgRNAs could exhibit enhanced penetration into tumors with increased gene editing of PD-L1 for improved cancer therapy. (c) Representative fluorescence microscopy images at 0 h (top) and 48 h (bottom) and quantification of GFP fluorescence intensity. Reproduced from ref. [44]. Copyright Nature Publishing Group.

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  Figure 4. (a) Endosomal escape: A bottleneck for LNP-mediated therapeutics. Reproduced from ref. [48]. Copyright NAS. (b) Rational design of cationic lipids for siRNA delivery. Reproduced from ref. [11]. Copyright Nature Portfolio. (c) Nanomechanical action opens endo-lysosomal compartments. Reproduced from ref. [32]. Copyright Nature Portfolio.

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  Figure 5. (a,b) A LNP platform incorporating trehalose glycolipid for exceptional mRNA vaccine safety. Reproduced from ref. [33]. Copyright KeAi Communications Co., Ltd. (c) Polysarcosine-functionalized LNPs for therapeutic mRNA delivery. Reproduced from ref. [34]. Copyright ACS.

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  Figure 6. (a) Carrier-free mRNA vaccine induces robust immunity against SARS-CoV-2 in mice and non-human primates without systemic reactogenicity. Reproduced from ref. [65]. Copyright Cell Press. (b) Biomimetic noncationic LNPs for mRNA delivery. The red dashed circle, the NC-TNP binds to mRNA via hydrogen bonds. Reproduced from ref. [35]. Copyright NAS. (c) LNP and NC-TNP complexed with mRNA encoding EGFP incubated with DC2.4 cells to evaluate the EGFP protein expression by confocal microscopy images. Reproduced from ref. [35]. Copyright NAS. (d) Schematic illustration of the experiment design. C57BL/6 mice were subcutaneously or intramuscularly injected with c-LNP, i-LNP, and NC-TNP. After different times, the skin samples from the injection site were collected for analysis. Reproduced from ref. [35]. Copyright NAS.

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  Figure 7. (a) MyD88-dependent and TRIF-dependent pathways signaling through TLRs activates intracellular signaling cascades that lead to nuclear translocation of AP-1 and NF-κB or IRF3. (b) Following IL-6 binding, the signal is transduced by a receptor to activate the JAKs, which then activate STATs. STATs are dephosphorylated in the nucleus, leading to the activation of downstream cytokines. Reproduced from ref. [68]. Copyright Impact Journals.