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Production Methods of LNP and Microfluidic Technique

Conventional method to produce lipid nanoparticles involves either high-pressure homogenization, or precipitation from both microemulsions and emulsions containing organic solvents. These methods require careful control of various process parameters: temperature, pressure, solvent toxicity, and emulsifier concentration. However, heat and cavitation impose significant thermodynamic and mechanical stress on the final product, while high concentrations of emulsifiers and residual solvents pose application challenges. 

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The alternative of microfluidic technique relies on hydrophobic and electrostatic interactions between solutes dissolved in two miscible solvents. This method offers distinct advantages over existing techniques, including the use of pharmaceutically acceptable organic solvents, elimination of high-pressure homogenization, simplified handling, and rapid production without the need for complex equipment. To summarize the method is to induce electrostatic interactions between the nucleic acid and charged lipids and promote nanoparticle growth via hydrophobic interactions. 


Typically, lipids are dissolved in ethanol, an organic solvent miscible with water. They are swiftly combined with water or an aqueous buffer, facilitating hydrophobic interactions among the lipid tails and hydrogen bonding between their hydrophilic heads and the surrounding water molecules. Solid lipid nanoparticles (LNPs) emerge when the central core comprises a lipid matrix. For instance, charged lipids interacting with RNA may form a solid structure, enveloped by additional lipid molecules, creating a protective particle shielding RNA from nuclease degradation. To generate RNA-loaded LNPs, RNA can be dissolved in an aqueous buffer and promptly mixed with lipid solutions. During this process, interactions among the lipids' hydrophilic components aid in RNA encapsulation. Additionally, electrostatic attractions between the RNA's negatively charged phosphate backbone and the positively charged components of cationic or zwitterionic lipids can facilitate encapsulation. Controlled microfluidic techniques enable precise control over LNP particle size, yielding formulations of high quality.  

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