Advanced strategies for enhancing mRNA-lipid nanoparticles stability: molecular insights, stabilization techniques, and clinical applications.

Advancements in mRNA formulation and delivery systems have transformed biomedical research, with the recent success of mRNA vaccines highlighting the technology's immense clinical potential. Despite their clinical success, the global reach of these vaccines is hindered by the necessity for ultracold storage, which restricts accessibility in resource-constrained regions. Improving the stability of mRNA-Lipid Nanoparticles (LNPs) at higher temperatures could be crucial for mass vaccination efforts in future outbreaks. This review evaluates the molecular assembly of mRNA-LNP systems, specifically how electrostatic complexation, hydrophobic interactions, and Van der Waals forces govern internal architectural organization and physicochemical integrity. This dual framework reveals how optimizing molecular coordination enhances the stability necessary for clinical viability. Beyond initial assembly, advanced stabilization technologies (e.g., lyophilization, spray-freeze drying (SFD), and thin-film freeze-drying) are evaluated for their ability to preserve LNP structural integrity during long-term storage. Incorporating these thermostable formulations into microneedle arrays and targeted pulmonary delivery platforms establishes non-invasive routes that enhance mucosal and transdermal bioavailability and clinical efficacy. Bridging nanoscale biophysics and macro-scale stability, this review connects electrostatic complexation, lipid architecture, and hydrophobic interactions to enhanced mRNA-LNP efficacy and extended shelf-life across biopharmaceutical applications.