Lipid Nanoparticles for Nucleic Acid Delivery and Gene Therapy: A Comprehensive Review

Abstract

Introduction: Conventional drug delivery systems face significant limitations for nucleic acid therapeutics, including poor bioavailability, instability, and inefficient cellular uptake. Lipid nanoparticles have emerged as a transformative platform for nucleic acid delivery and gene therapy. These systems provide essential protection from degradation while enabling efficient cellular internalization and endosomal escape.

Methods: A systematic analysis of 45 publications (2004-2025) from National Institutes of Health and PubMed databases was conducted. This analysis evaluated lipid nanoparticle technologies for nucleic acid delivery, focusing on fundamental design principles, optimization strategies, and targeting mechanisms for gene therapy applications.

Results: This review identifies critical advances in lipid nanoparticle technology across three domains: fundamental design principles, optimization strategies, and targeting approaches. Lipid nanoparticles utilize pH-dependent endosomal escape mechanisms through ionizable lipids with optimized pKa values (6.2-6.5 for liver targeting, 6.6-6.9 for vaccines). Branched-tail lipidoid architectures demonstrate tenfold improved potency over linear analogs through enhanced endosomal ionization. Microfluidic manufacturing achieves >90% encapsulation efficiency with polydispersity indices ≤0.25. Clinical validation includes COVID-19 mRNA vaccines achieving >94% efficacy. Gene editing applications like VERVE-101 demonstrate sustained genetic modifications.

Discussion: Despite significant technological advances, challenges persist in manufacturing scalability, targeting specificity, and methodological standardization across diverse ionizable lipid libraries. Safety considerations require careful evaluation of dose-dependent toxicity profiles, while regulatory frameworks must address manufacturing scalability and quality control for gene therapy applications.

Conclusion: Lipid nanoparticle technology has revolutionized nucleic acid delivery and gene therapy through innovations in ionizable lipid design, manufacturing optimization, and targeting strategies. Critical challenges remain in targeting efficiency and endosomal escape mechanisms. Future developments should prioritize enhanced targeting specificity, improved biocompatibility, and standardized evaluation protocols to advance precision genetic therapeutics.