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[PharmNews=Eung-Min Kim] As nanotechnology for improving drug delivery efficiency advances rapidly, the manufacturing process of lipid nanoparticles(LNPs) is emerging as a critical factor determining therapeutic performance.

(From left) Hyeseon Park and Jaeseong Lee (School of Systems Biomedical Science, Soongsil University); Professor Jiwoo Hong (School of Mechanical Engineering, Soongsil University); and Professor Gayong Shim (School of Systems Biomedical Science, Soongsil University). (Photo=Soongsil University)

Following the widespread use of LNPs as carriers for nucleic acid medicines, such as the mRNA vaccines during the COVID-19 pandemic, the demand for more precise and efficient manufacturing technologies has grown significantly.

Possibility and Obstacles in Gene Expression Control

Nucleic acid therapeutics are looked forward to next-generation strategies because they can regulate gene expression which is a feat difficult to achieve with conventional small molecule or antibody drugs. mRNA therapeutics are based on the Central Dogma, these allow cells to directly express therapeutic proteins.

siRNAs are bind complementarily to target mRNA, forming the RNA-induced silencing complex (RISC) to induce RNA interference(RNAi), selectively inhibiting specific gene expression. Despite their potential, nucleic acids face significant hurdles.

They have a negative charge from their phosphate backbone, making it difficult to spontaneously cross cell membranes, and they are rapidly degraded by nucleases in the body. Therefore, a robust delivery vehicle is essential to stabilize and transport these molecules into target cells.

Convergence of 3D Printing and Microfluidics

A research team has confirmed that microfluidic technology can produce LNPs with superior uniformity and performance compared to conventional methods. By precisely controlling the size and structure of the nanoparticles, the team demonstrated the potential to simultaneously enhance drug delivery efficiency and stability.

The joint research team, led by Prof. Shim(School of Systems Biomedical Science) and Prof. Hong (School of Mechanical Engineering) at Soongsil University, utilized a 3D printing-based microfluidic chip process to manufacture cationic LNPs. They compared these with liposomes created via the traditional thin film hydration method.

Liposomes, characterized by a lipid bilayer, are typically produced via the thin-film hydration method, which ｒｅｑｕｉｒｅs post processing steps like sonication or extrusion to achieve the desired size. In contrast, Lipid Nanoparticles (LNPs) are synthesized through a self-assembly process using microfluidic technology. The micromixers within the system create vortices that ensure uniform mixing of lipids and nucleic acids, enabling the production of monodisperse particles without additional post processing. It is a critical factor for effective drug delivery.

Confirmation of Uniform Particle Control and Low Cytotoxicity

LNPs possess a structure similar to cell membranes, offering high biocompatibility and the ability to effectively deliver therapeutics, such as nucleic acids, into cells. However, conventional manufacturing methods have long faced challenges due to complex processes and limitations in ensuring consistent particle size and uniformity.

The research team addressed these hurdles by utilizing a microfluidic system equipped with internal mixers that ensure the even blending of lipids and nucleic acids. They confirmed that by adjusting flow rates and lipid concentrations, the size of the nanoparticles could be precisely controlled.

Under optimal conditions, the team stably produced uniform particles under 100 nm, a critical size threshold that significantly impacts drug delivery efficiency and distribution within the body.

Furthermore, the study revealed that these microfluidic based LNPs demonstrated gene delivery efficiency comparable to conventional liposomes but with lower cytotoxicity. In animal models, the particles exhibited prolonged retention times, suggesting that this technology could contribute to the sustained therapeutic effects of the drug.

Leap to a Next-Generation Nucleic Acid Delivery Platform

"The microfluidic based manufacturing method is a technology capable of simultaneously controlling the size, structure, and drug loading efficiency of nanoparticles," the researchers stated. "It will serve as an important platform for developing next-generation nucleic acid delivery systems and nanomedicines."

The study, co-authored by researchers Hyeseon Park and Jaeseong Lee from Prof. Shim’s team and Prof. Hong’s team, was published in the international pharmacy journal, Journal of Pharmaceutical Investigation(IF=5.3).

Eung-Min Kim