RNA-based therapeutics have shown
great promise in treating a broad
spectrum of diseases through various mechanisms including knockdown
of pathological genes, expression of therapeutic proteins, and programmed
gene editing. Due to the inherent instability and negative-charges
of RNA molecules, RNA-based therapeutics can make the most use of
delivery systems to overcome biological barriers and to release the
RNA payload into the cytosol. Among different types of delivery systems,
lipid-based RNA delivery systems, particularly lipid nanoparticles
(LNPs), have been extensively studied due to their unique properties,
such as simple chemical synthesis of lipid components, scalable manufacturing
processes of LNPs, and wide packaging capability. LNPs represent the
most widely used delivery systems for RNA-based therapeutics, as evidenced
by the clinical approvals of three LNP-RNA formulations, patisiran,
BNT162b2, and mRNA-1273. This review covers recent advances of lipids,
lipid derivatives, and lipid-derived macromolecules used in RNA delivery
over the past several decades. We focus mainly on their chemical structures,
synthetic routes, characterization, formulation methods, and structure–activity
relationships. We also briefly describe the current status of representative
preclinical studies and clinical trials and highlight future opportunities
and challenges.
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