Lipidoids

Lipidoids are a class of lipid-like molecules designed for nucleic acid delivery. They are typically amphiphilic, with hydrophobic tails and a cationic or tertiary amine-containing head group. Lipidoids are commonly generated by a modular, combinatorial synthesis in which diverse amines are added to acrylate or acrylamide scaffolds, producing libraries of structures. This tunability allows researchers to adjust properties such as pKa, hydrophobicity, and molecular geometry to influence cellular uptake and endosomal escape.

Formulations that incorporate lipidoids usually assemble into lipid-like nanoparticles (LNPs) with cholesterol and helper lipids, and often polyethylene glycol (PEG) conjugates to improve stability and circulation. The resulting particles encapsulate nucleic acids such as siRNA or mRNA. After uptake by cells, the protonation of the head groups can promote endosomal disruption and release of cargo into the cytoplasm.

Applications and significance: Lipidoids have been explored as non-viral delivery platforms for gene silencing and gene expression, enabling studies in vitro and in vivo and contributing to the broader development of RNA therapeutics and vaccines. They are seen as a complementary approach to conventional lipid-based delivery systems, offering a flexible design space for optimization.

Limitations and challenges include toxicity at higher doses, inflammatory responses, stability during storage and in circulation, and the need for targeted delivery. Ongoing research aims to improve safety profiles, biodistribution, and manufacturing scalability.