ArticleProceedings of the National Academy of Sciences of the United States of America2023
Combinatorial design of ionizable lipid nanoparticles for muscle-selective mRNA delivery with minimized off-target effects.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 120 citations in OpenAlex.
- Delivering the blueprint: Advances and challenges in mRNA therapeutics for the respiratory system.International journal of pharmaceutics: X · 2026Review
- Optimization of lipid nanoparticles reduces hepatic accumulation and enhances local delivery of mRNA.Science China. Life sciences · 2026Article
- Revisiting the lipid ratio in lipid nanoparticles: A comparison of OFAT and design of experiments approaches.Drug delivery and translational research · 2026Article
- Bioactive lipid-derived nanoparticles for RNA delivery.Materials today (Kidlington, England) · 2026Article
- Lipid nanoparticles optimized for large RNA cargo and tissue targeting enhance in vivo genome editing.Nature biotechnology · 2026Article
- Spatiotemporal control of STING activation and saRNA delivery decouples humoral and cellular immunity.bioRxiv : the preprint server for biology · 2026Article
- X-linked myotubular myopathy, liver disease, and gene therapy.Journal of neuromuscular diseases · 2026Review
- Lipid nanoparticles as active biointerfaces: From membrane interaction to systemic dysregulation.Acta pharmaceutica Sinica. B · 2026Review
- Hydrophobic Tail and Linker Diversification of PEG-Lipids Unlocks Precise Muscle Tropism of mRNA-Lipid Nanoparticles.Small (Weinheim an der Bergstrasse, Germany) · 2026Article
- Recent Advances in Lipid Nanoparticle-Mediated Respiratory and Gastrointestinal Mucosal Delivery of Nucleic Acids.Bioengineering (Basel, Switzerland) · 2026Review
- Review
- SORT LNPs encapsulating Cas9 mRNA achieve efficient editing in skeletal muscle in a dystrophic mouse model.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Analytical Characterization and Stability Assessment of RNA-Based Vaccines.Pharmaceutics · 2026Review
- DNA-directed assembly of multivalent lipid nanoparticles for targeted T cell gene delivery.Journal of controlled release : official journal of the Controlled Release Society · 2026Article
- Antioxidant lipid nanoparticles enhance mRNA stability for regeneration therapy and gene editing.Nature communications · 2026Article
- Poly(I:C) Lipoamino Bundle LNPs Induce Tumor Cytotoxicity and Immune Activation with Enhanced Efficacy by Survivin Silencing.International journal of molecular sciences · 2026Article
- Ionizable Polymeric Micelles Targeting Transferrin Receptor 1 Enhance Systemic mRNA Delivery to the Brain.Molecular pharmaceutics · 2026Article
- A multiobjective AI model for LNP engineering enhances tissue-selective mRNA delivery.Nature biotechnology · 2026Article
- A poorly reactogenic lipid nanoparticle-mRNA vaccine unveils an innate immune pathway for adverse reactions.NPJ vaccines · 2026Article
- Gauging lipid vulnerabilities in mRNA-LNPs under various environmental stressors through TIMS-TOF analysis.RSC advances · 2026Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Ionizable lipid nanoparticles (LNPs) pivotal to the success of COVID-19 mRNA (messenger RNA) vaccines hold substantial promise for expanding the landscape of mRNA-based therapies. Nevertheless, the risk of mRNA delivery to off-target tissues highlights the necessity for LNPs with enhanced tissue selectivity. The intricate nature of biological systems and inadequate knowledge of lipid structure-activity relationships emphasize the significance of high-throughput methods to produce chemically diverse lipid libraries for mRNA delivery screening. Here, we introduce a streamlined approach for the rapid design and synthesis of combinatorial libraries of biodegradable ionizable lipids. This led to the identification of iso-A11B5C1, an ionizable lipid uniquely apt for muscle-specific mRNA delivery. It manifested high transfection efficiencies in muscle tissues, while significantly diminishing off-targeting in organs like the liver and spleen. Moreover, iso-A11B5C1 also exhibited reduced mRNA transfection potency in lymph nodes and antigen-presenting cells, prompting investigation into the influence of direct immune cell transfection via LNPs on mRNA vaccine effectiveness. In comparison with SM-102, while iso-A11B5C1's limited immune transfection attenuated its ability to elicit humoral immunity, it remained highly effective in triggering cellular immune responses after intramuscular administration, which is further corroborated by its strong therapeutic performance as cancer vaccine in a melanoma model. Collectively, our study not only enriches the high-throughput toolkit for generating tissue-specific ionizable lipids but also encourages a reassessment of prevailing paradigms in mRNA vaccine design. This study encourages rethinking of mRNA vaccine design principles, suggesting that achieving high immune cell transfection might not be the sole criterion for developing effective mRNA vaccines.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.