Lipid Nanoparticles—From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement

Purpose: Lipid nanoparticles (LNPs) have become key delivery vehicles across pharmaceuticals, with renewed prominence as the delivery platform for COVID-19 mRNA vaccines. The field lacks a broad, quantitative landscape of LNP research across liposomes, solid lipid nanoparticles, nanostructured lipid carriers, cationic lipid–nucleic acid complexes, and newer architectures. This review provides an overview of LNP structures, properties, applications, and global research trends based on the CAS Content Collection.

Hypothesis: As a review and bibliometric analysis, there is no single experimental hypothesis. Central thesis: LNPs—from early liposomes to modern ionizable cationic lipid nanoparticles—constitute a versatile and expanding nanomedicine platform; quantitative analysis of the CAS Content Collection can reveal research trends, dominant formulation types, chemical components, applications, and translational progress, especially for nucleic acid therapeutics and mRNA vaccines.

Aims: Provide an overview of LNP structures and properties from a pharmaceutical applications viewpoint. - Discuss multiple LNP applications: drug and vaccine delivery, medical imaging, cosmetics, nutrition, agriculture, nanoreactors, and membrane models. - Present a landscape of LNP-related research using the CAS Content Collection, including publications and patents by time, research area, formulation, application, and chemical composition. - Identify the most widely used chemical substances in LNP formulations, including phospholipids, PEG-lipids, and cationic lipids. - Evaluate challenges and growth opportunities for LNP technologies.

Delivery system: Platform types: liposomes (SUVs, LUVs, GUVs, MLVs), solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), cationic lipid–nucleic acid complexes/lipoplexes, cubosomes, hexosomes, micelles, ethosomes, echogenic liposomes, immunoliposomes, “stealth”/PEGylated liposomes, stimuli-responsive liposomes. - Payloads: small molecules, proteins, nucleic acids (pDNA, siRNA, mRNA), vaccines, imaging agents, cosmetics, nutraceuticals, agrochemicals. - Key lipid components: phospholipids (PC, PE, PG, PS), cholesterol, PEG-lipids (PEG-PE, DPPE-PEG, DOPE-PEG, DMG-PEG, DSPE-mPEG, ALC-0159), cationic/ionizable lipids (DOTAP, DOTMA, DC-Chol, DDAB, DODAP, DLinDMA, DLin-MC3-DMA, DLin-KC2-DMA, SM-102, ALC-0315). - COVID-19 mRNA vaccine LNPs: BNT162b2 (Pfizer/BioNTech) uses ALC-0315, ALC-0159, DSPC, cholesterol; mRNA-1273 (Moderna) uses SM-102, PEG2000-DMG, DSPC, cholesterol. - Targeting ligands: folate, transferrin, GM-CSF, RGD, NGR, anti-VEGFR, anti-ERBB2, anti-CD20, anti-CD22, anti-CD33, anti-CD25, anti-tenascin, anti-MUC1, anti-TAG72, anti-CEA.

Approach: Review and quantitative bibliometric analysis of the CAS Content Collection. Over 216,000 LNP-related scientific publications were identified, including patents and non-patents; over 170,000 were from 2000–2020. More than 45,000 patents related to LNPs/liposomes were identified, over 41,000 from 2000–2021. Documents were classified by time, research area, LNP type, delivery route, target disease, therapy, patent office, country, and organization. The review also summarizes approved LNP drugs, clinical trials of mRNA drugs/vaccines, marketed cosmetic preparations, and lipid constituents of COVID-19 mRNA vaccines. Not a primary experimental study.

Key methods: CAS Content Collection curation and quantitative analysis; classification of documents by research area, formulation, application, chemical composition, patent office, country, and organization; identification of most widely used lipids via patent counts; timeline of liposome/LNP advancement; tables of approved LNP formulations, clinical trials, and COVID-19 vaccine lipid components; analysis of delivery routes, target diseases, and LNP type–therapy correlations.

Key results: LNP research is dominated by pharmaceutical applications. The fastest-growing research areas are pharmaceuticals, food and feed, and cosmetics. - The term “liposome” appears in ~147,000 documents from 2000–2020, versus ~26,000 for “lipid nanoparticle”; immunoliposomes and cationic liposomes are the largest LNP subcategories, while SLN, cubosomes, and especially NLC show the fastest growth. - Antitumor LNP formulations dominate drug-delivery documents; the largest single use is breast cancer (>25%), followed by ovarian and lung cancers (>10% each). - Delivery routes: parenteral 43%, oral 20%, topical/transdermal 17%, nasal 5%, ocular 3%, pulmonary 3%, rectal 2%, vaginal 2%. - Cholesterol is the most widely used lipid component, appearing in over 3,200 patents. Common phospholipids include saturated 14:0/14:0, 16:0/16:0, 18:0/18:0, and unsaturated 18:1c9/18:1c9 chains. Common PEG-lipids include PEG-PE, DPPE-PEG, DOPE-PEG, DMG-PEG, DSPE-mPEG, and Chol-PEG. Common cationic lipids include DOTAP, DOTMA, DC-Chol, DDAB, DLinDMA, DLin-MC3-DMA, SM-102, and ALC-0315. - Approved LNP drugs include Doxil (earliest approved liposomal drug), Epaxal (hepatitis vaccine), Onpattro (first FDA-approved LNP-based siRNA drug), and LNP-based mRNA vaccines for COVID-19. - Cationic lipid toxicity depends on head group: quaternary ammonium head groups are more toxic than tertiary amine head groups. Ionizable lipids are preferred because they are positively charged inside cells but uncharged in the bloodstream. - Parenteral particles generally need to be ≤100 nm; zeta potentials < −30 mV or >30 mV are generally sufficient for stable suspensions. - Microfluidic synthesis enabled nanoscale liposomes encapsulating siRNA that achieved 50% target gene silencing in hepatocytes at a dose of 10 µg/kg siRNA in mice.

Interpretation: LNPs are one of the most advantageous and promising areas in modern nanotechnology. Liposomes were the earliest nanomedicine delivery platform to successfully proceed from concept to clinical application, and subsequent generations—SLN, NLC, and cationic lipid–nucleic acid complexes—offer enhanced physical stability and more complex architectures. The COVID-19 mRNA vaccines have dramatically highlighted the clinical potential of LNPs. LNPs hold great promise in genetic medicine, vaccine development, immuno-oncology, and precision medicine. Continued synthesis and screening of functionalized lipid nanomaterials, with tunable biodegradability and multifunctional designs, should promote more versatile, efficient, and biocompatible delivery vehicles. Challenges include cationic lipid toxicity, stability, cargo release, scale-up, and regulatory considerations.

Limitations: This is a review and bibliometric analysis, not a primary experimental study. CAS Content Collection coverage and terminology changes over time (e.g., “liposome” vs “lipid nanoparticle”) may affect quantitative trends. No new experimental validation is provided. Clinical translation of LNP-based gene therapy remains limited; DNA delivery to the nucleus is a barrier, whereas RNA therapeutics only require cytoplasmic delivery. Toxicity and immunogenicity of cationic lipids and PEG-lipids remain concerns. Long-term stability, manufacturing scalability, and regulatory challenges are not fully resolved. The review focuses on CAS-indexed documents and is not a comprehensive systematic review of all LNP literature.