Introduction

The past five years have witnessed significant progress in the field of lipid nanoparticle (LNP)-mediated mRNA delivery. This mini-review focuses on recent advancements in LNP engineering, specifically targeting strategies for tissue-specific delivery and methods to enhance the immunogenicity of mRNA vaccines. We will explore the evolution of LNP design, highlighting key findings and emerging trends in the field.

Targeted mRNA Delivery via LNP Engineering

A major focus in LNP research is achieving targeted delivery of mRNA to specific tissues and cell types. This is crucial for both therapeutic applications, such as gene editing and cancer therapy, and for improving the efficacy and reducing the side effects of mRNA vaccines.

Selective Organ Targeting (SORT): Daniel J. Siegwart's group at Northwestern University has pioneered the development of selective organ targeting (SORT) nanoparticles. Their work in 2020 demonstrated the feasibility of tissue-specific mRNA delivery using SORT LNPs and CRISPR-Cas gene editing (Qiang Cheng et al., 2020, Nature Nanotechnology). Further studies by the Siegwart group elucidated the mechanisms underlying tissue specificity (Sean A. Dilliard et al., 2020, Proceedings of the National Academy of Sciences; Sean A. Dilliard et al., 2021, Proceedings of the National Academy of Sciences) and explored the use of membrane-destabilizing ionizable phospholipids for enhanced delivery and gene editing (Shuai Liu et al., 2020, Nature Materials; Shuai Liu et al., 2021, Nature Materials). In 2022, the Siegwart group published a detailed protocol for preparing SORT LNPs using various technical methods (Xu Wang et al., 2022, Nature Protocols). More recently, in 2024, the Siegwart group has demonstrated bone-marrow-homing LNPs for genome editing in hematopoietic stem cells (Xizhen Lian et al., 2024, Nature Nanotechnology).

Lung-Targeted Delivery: Several research groups have focused on developing LNPs for lung-specific mRNA delivery. Qiaobing Xu at Stony Brook University demonstrated lung-selective mRNA delivery for the treatment of pulmonary lymphangioleiomyomatosis (LAM) (Min Qiu et al., 2020, Proceedings of the National Academy of Sciences; Min Qiu et al., 2021, Proceedings of the National Academy of Sciences; Min Qiu et al., 2022, Proceedings of the National Academy of Sciences). James E. Dahlman's group at Georgia Institute of Technology optimized LNPs for nebulized delivery of therapeutic mRNA to the lungs (Melissa P. Lokugamage et al., 2021, Nature Biomedical Engineering). Daniel G. Anderson's group at MIT has explored combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing (Bowen Li et al., 2022, Nature Biotechnology; Bowen Li et al., 2023, Nature Biotechnology) and developed nebulized mRNA delivery formulations for the lungs (Allen Yujie Jiang et al., 2023, Nature Nanotechnology). Michael J. Mitchell's group at the University of Pennsylvania has also contributed to this area, developing high-throughput barcoding methods to identify lipid-like materials for mRNA delivery to the lungs (Lulu Xue et al., 2024, Nature Communications). Gaurav Sahay's group at the University of Nebraska Medical Center has engineered LNPs for enhanced intracellular delivery of mRNA through inhalation (Jeonghwan Kim et al., 2022, ACS Nano) and developed thiophene-based lipids for mRNA delivery to pulmonary and retinal tissues (Yulia Eygeris et al., 2024, Proceedings of the National Academy of Sciences).

Other Tissue-Specific Targeting: Researchers have also explored LNP-mediated mRNA delivery to other specific tissues. Hyukjin Lee's group at Sungkyunkwan University engineered ionizable LNPs for targeted delivery of RNA therapeutics to different types of cells in the liver (M. Kim et al., 2021, Science Advances). Michael J. Mitchell's group has also investigated mRNA delivery to the placenta during pregnancy (Kelsey L. Swingle et al., 2022, Journal of the American Chemical Society; Kelsey L. Swingle et al., 2023, Journal of the American Chemical Society) and the bone microenvironment (Lulu Xue et al., 2022, Journal of the American Chemical Society). Kathryn A. Whitehead's group at Carnegie Mellon University has shown that LNPs can deliver mRNA to pancreatic β cells via macrophage-mediated gene transfer (Jilian R. Melamed et al., 2023, Science Advances). Marco Herrera and Gaurav Sahay's groups have developed peptide-guided LNPs for mRNA delivery to the neural retina (Marco Herrera et al., 2023, Science Advances). Shuai Liu's group at the University of Texas at Austin has developed one-component cationic lipids for systemic mRNA delivery to splenic T cells (Xinyue Zhang et al., 2024, Angewandte Chemie International Edition) and reformulating LNPs for organ-targeted mRNA accumulation and translation (Kexin Su et al., 2024, Nature Communications).

Enhancing Immunogenicity of mRNA Vaccines

Another critical area of LNP research focuses on enhancing the immunogenicity of mRNA vaccines. This involves optimizing LNP composition and structure to improve mRNA delivery to immune cells and stimulate a robust immune response.

Adjuvanting LNPs: Michael J. Mitchell's group has explored the use of adjuvant lipidoid-substituted LNPs to augment the immunogenicity of SARS-CoV-2 mRNA vaccines (Xuexiang Han et al., 2023, Nature Nanotechnology). Daniel G. Anderson's group has also investigated enhancing the immunogenicity of LNP mRNA vaccines by adjuvanting the ionizable lipid and the mRNA (Bowen Li et al., 2023, Nature Biomedical Engineering).

LNP Structure and Composition: Gaurav Sahay's group has investigated the role of naturally occurring cholesterol analogues in LNPs, finding that they induce polymorphic shape and enhance intracellular delivery of mRNA (Siddharth Patel et al., 2020, Nature Communications). Miffy H. Y. Cheng and Pieter R. Cullis's groups have shown that induction of bleb structures in LNP formulations of mRNA leads to improved transfection potency (Miffy H. Y. Cheng et al., 2022, Advanced Materials; Miffy H. Y. Cheng et al., 2023, Advanced Materials).

Conclusion

The field of LNP-mediated mRNA delivery has experienced rapid advancements in recent years. Researchers are developing increasingly sophisticated strategies for targeted delivery to specific tissues and cell types, as well as methods to enhance the immunogenicity of mRNA vaccines. These advancements hold great promise for the development of new therapies and vaccines for a wide range of diseases. Future research will likely focus on further optimizing LNP design, improving our understanding of LNP-cell interactions, and addressing challenges such as endosomal escape (Sushmita Chatterjee et al., 2024, Proceedings of the National Academy of Sciences) and potential immune responses to LNP components.

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