Targeting the stability of lipid nanoparticles!

Targeting lipid nanoparticles (LNPS) in vivo involves complex environments, including enzymes, proteins, pH ranges from 2 to 10, hypoxia, and reducing agents. These factors can affect the stability of targeted LNP and thus its effect in vivo.

Cationic or ionizable lipid nanoparticles are commonly used for nucleic acid encapsulation, but they tend to adsorb natural proteins in circulation and form a protein crown that inhibits receptor recognition and accelerates LNPclean up. In addition, the coupling of targeted ligands can change the surface properties of LNP and even trigger the aggregation of targeted ligands at high concentrations. Therefore, nanoparticle size and stability dynamics are commonly used to evaluate the stability of targeted LNPS, for example by gel electrophoresis to examine nucleic acid/protein degradation in physiological environments.

To improve the stability of LNP, PEGylation is often used to reduce the formation of protein crowns and prolong the circulation time of LNP in the blood. However, PEG is a synthetic polymer and is not degradable. Its autoimmunogenicity and the high presence of anti-PEG antibodies in the body may affect the treatment effect and induce cytotoxicity. Recently, more efforts have been made to develop materials that can replace PEG to improve the stability of targeting LNP and extend its circulation time in vivo, while being degraded to eliminate concerns about immunogenicity. These efforts are aimed at finding more sustainable alternative materials to optimize LNP design and performance.

In addition, the long-term storage of targeted lipid nanoparticles, especially those loaded with biomolecules such as proteins or nucleic acids, is another bottleneck for market applications. Natural lipids are usually biodegradable and will be oxidized in aqueous solutions over time. Lipids, meanwhile, are heat-sensitive molecules. Their melting temperature affects the transition from gel to liquid, while the glass transition temperature indicates that the higher-order lipid bilayer changes into a random conformation. Currently, most lipid nanoparticles have a very short shelf life. At room temperature, the SirNA-encased lipid nanoparticles completely lost their gene-silencing activity after 156 days. Lyophilized formulations can slightly extend shelf life while limiting oral accessibility. Novel stable lipids with disease-matching transition temperatures and high delivery efficiency are urgently needed. At the same time, formulations supplemented with cryoprotectants and stabilizers are an alternative solution to extend the shelf life of targeted lipid nanoparticles.

About AVT

Aivito is a service pharmaceutical technology company with products covering natural phospholipids, synthetic phospholipids, functionalized phospholipids, nucleic acid delivery segments, and related excipients such as oleic acid, sodium oleate, cholesterol, trehalose (for injection), sucrose (for injection), etc. AVT focuses on drug delivery systems such as liposomes, fat milk, micro and nano targeting preparations, and is the main phospholipid supplier of domestic pharmaceutical companies, universities, research institutes and other units.