Lipid Nanoparticles for mRNA and siRNA Delivery: Formulation Design, Ionizable Lipid Optimization, and Therapeutic Applications

Abstract

Background: Lipid nanoparticles (LNPs) have rapidly become the most clinically validated non-viral platform for the delivery of nucleic acid therapeutics, culminating in the global deployment of mRNA-based COVID-19 vaccines. The inherent instability of messenger RNA (mRNA) and small interfering RNA (siRNA) in biological fluids, their impermeability across cellular membranes, and susceptibility to enzymatic degradation demand robust encapsulation within structurally sophisticated nanocarriers. LNPs fulfill these requirements through their four-component lipid architecture and unique capacity to facilitate endosomal escape, enabling cytosolic delivery of functional nucleic acids with high efficiency.

Objective: This review critically appraises the formulation principles, lipid component optimization, manufacturing methodologies, characterization strategies, mechanisms of intracellular delivery, and therapeutic applications of LNPs for mRNA and siRNA delivery, with particular emphasis on recent research findings and their translational significance.

Results and Discussion: The LNP architecture comprising an ionizable lipid, helper phospholipid, cholesterol, and PEG-lipid enables efficient nucleic acid encapsulation, systemic circulation, cellular uptake, and endosomal membrane disruption. Ionizable lipid pKa values between 6.2 and 6.8 are critical determinants of in vivo potency. Clinically approved systems including patisiran for siRNA delivery and the COVID-19 mRNA vaccines BNT162b2 and mRNA-1273 have validated this platform at a population scale. Emerging directions including organ-selective LNPs, self-amplifying mRNA, and circular RNA further expand the therapeutic reach of this technology.

Conclusion: LNPs represent a transformative pharmaceutical platform for nucleic acid delivery with demonstrated clinical efficacy across infectious disease, hereditary disorders, and oncology. Continued innovation in lipid design, manufacturing scalability, and extrahepatic targeting will define the next generation of RNA medicines.