Lipid Nanoparticles Beyond mRNA Vaccines: Emerging Therapeutic Applications, Formulation Strategies and Translational Challenges

Abstract

Lipid nanoparticles (LNPs) rose to global prominence as the delivery platform underpinning the messenger RNA (mRNA) vaccines deployed during the COVID-19 pandemic, yet their therapeutic potential extends far beyond prophylactic vaccination. This review examines the expanding landscape of LNP applications, situating the well-characterised four-component architecture—ionisable lipid, helper phospholipid, cholesterol and polyethylene glycol (PEG)-lipid—within a broader therapeutic context that now encompasses small interfering RNA (siRNA) therapeutics, gene editing payloads, protein-replacement mRNA, small-molecule chemotherapeutics and emerging in vivo cell-engineering strategies (Hou et al., 2021). We synthesise evidence describing how each formulation component governs particle self-assembly, apparent pKa, endosomal escape and organ tropism, and we highlight how rational lipid design and manufacturing advances such as microfluidic mixing have improved encapsulation efficiency, reproducibility and scalability (Evers et al., 2018; Schoenmaker et al., 2021). The review is organised around four thematic pillars: the physicochemical determinants of LNP behaviour, the diversification of nucleic-acid and small-molecule cargoes, strategies for extrahepatic and targeted delivery, and the translational barriers that continue to constrain clinical adoption. Persistent challenges include hepatic accumulation that limits delivery to other tissues, cold-chain stability requirements, batch-to-batch heterogeneity, PEG-associated immunogenicity, and incompletely understood long-term safety profiles (Tenchov et al., 2021; Kularatne et al., 2022). Drawing on 28 peer-reviewed sources published between 2015 and 2024, this narrative review argues that the convergence of ionisable-lipid chemistry, targeting ligands and continuous manufacturing positions LNPs as a versatile modular platform likely to enable a new generation of genetic medicines. We conclude by outlining priority directions, including biodegradable lipid libraries, organ-selective SORT formulations, lyophilisation for ambient stability, and closed-loop good manufacturing practice (GMP) production.