Polysorbate 80-containing ionizable lipid nanoparticles for mRNA delivery†

Ionizable lipid nanoparticles have demonstrated remarkable success as mRNA vaccine carriers and represent one of the most promising gene drug delivery vehicles. However, polyethylene glycol (PEG), one of the major components, can cause immunogenic reactions, anaphylaxis and increased blood clearance, leading to toxic side effects and reduced efficacy. In this study, we utilize polysorbate 80 (PS80) as a PEG alternative in formulating eGFP mRNA-loaded ionizable lipid nanoparticles (PS80-iLNPs), aiming to enhance stealth properties, uptake efficiency, and biosafety. Our findings revealed that PS80-iLNPs enhanced the stealthiness and resistance to serum interference. Compared to PEG-containing ionizable lipid nanoparticles (PEG-iLNPs), PS80-iLNPs showed a 1.14-fold increase in stealthiness. Moreover, at a total lipid concentration of 50 μg mL⁻¹, PS80-iLNPs exhibited 1.12 times higher cell viability compared to PEG-iLNPs. Notably, under serum interference, PEG-iLNPs showed a 44.97% uptake reduction, whereas PS80-iLNPs exhibited a modest 30.55% decrease, underscoring its superior serum resistance. This work demonstrated that PS80 could serve as a suitable substitute for PEG, thus signifying an excellent basis for the development of PEG-free ionizable lipid nanoparticles.