Advanced materials (Deerfield Beach, Fla.)Oct 19, 2026

New Lipid Nanoparticle Methods for Delivering RNA Treatments Outside the Liver

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 20, 2026

Abstract

Lipid nanoparticles (LNPs) could enhance RNA delivery to tissues beyond the liver, including the spleen, lungs, lymph nodes, brain, and tumors.

Conventional LNPs have an inherent preference for the liver, limiting their effectiveness in targeting other tissues.
Recent advancements in lipid chemistry and particle engineering may enable the redirection of LNPs to specific tissues and cell types.
Key factors affecting LNP tropism include formulation composition, surface characteristics, protein interactions, and the method of administration.
Challenges in clinical translation include understanding biodistribution at the cellular level, ensuring long-term safety, and assessing immunogenicity.
Technological innovations like high-throughput screening and machine learning may improve the design and optimization of future LNPs.

Simplified

Lipid nanoparticles (LNPs) have transformed RNA therapeutics through their high delivery efficiency, scalable manufacturing, and favorable safety profiles, as demonstrated by COVID-19 mRNA vaccines and clinically approved small interfering RNA (siRNA) therapeutics. However, extending RNA delivery beyond the liver to extrahepatic tissues, including the spleen, lungs, lymph nodes, brain, and tumors, remains challenging because of the intrinsic hepatotropism of conventional LNPs and their limited cell-type specificity. Recent advances in lipid chemistry, particle engineering, surface functionalization, protein corona modulation, and route-specific administration have enabled new strategies to redirect LNPs toward specific tissues and cell populations. This review systematically examines these approaches and highlights key determinants of LNP tropism, including formulation composition, surface properties, endogenous protein adsorption, and administration route. We further discuss the clinical translation of extrahepatic LNP delivery, covering clinically validated products, emerging therapeutic candidates, and gaps between preclinical models and human applications. Major challenges include cell-resolved biodistribution, long-term safety, repeated-dose immunogenicity, cross-study comparability, and standardized quantitative assessment. Finally, we explore how high-throughput screening, machine learning, and data-driven design can accelerate the rational optimization of next-generation LNPs. These advances may facilitate precise tissue- and cell-selective RNA delivery, expanding the therapeutic potential of RNA medicines beyond the liver.

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New Lipid Nanoparticle Methods for Delivering RNA Treatments Outside the Liver

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