Development of a concentration‐controlled sequential nanoprecipitation for making lipid nanoparticles with high drug loading

Lipid‐based nanostructures have garnered considerable interests over the last two decades, and have achieved tremendous clinical success including the first clinical approval of a liposome (Doxil) for cancer therapy in 1995 and the recent COVID‐19 mRNA lipid nanoparticle vaccines. Compared to liposomes which have a lipid bilayer surrounding an aqueous core, lipid nanoparticles with a particle structure have several attractive advantages for encapsulating poorly water‐soluble drugs such as better stability due to the particle structure, high drug encapsulation efficiency because of a pre‐ or co‐drug‐loading strategy. While many studies have reported the synthesis of lipid nanoparticles for hydrophobic drug encapsulation, the precise control of drug loading and encapsulation efficiency remains a significant challenge. This work reports a new concentration‐controlled nanoprecipitation platform technology for fabricating lipid nanoparticles with tunable drug loading up to 70 wt%. This method is applicable for encapsulating a wide range of drugs from very hydrophobic to slightly hydrophilic. Using this facile method, nanoparticles with tunable drug loading exhibited excellent properties such as small particle size, narrow size distribution, good particle stability, showing great promise for future drug delivery applications.