Thermoresponsive Poly(glycidyl ether)-Modified Lipid Nanoparticles as a PEG Alternative for Temperature-Dependent Stealth Modulation and mRNA Delivery

Lipid nanoparticles (LNPs) are clinically important carriers for messenger RNA (mRNA), but poly(ethylene glycol) (PEG) can induce anti-PEG antibodies, accelerated blood clearance, and complement-associated immune responses, limiting repeated administration. Here, thermoresponsive poly(glycidyl ether) (PGE) derivatives were developed as PEG alternatives for polymer–lipid hybrid LNPs. PGE polymers were synthesized by anionic ring-opening polymerization with controlled molecular weights and narrow dispersity, as confirmed by ¹H nuclear magnetic resonance spectroscopy, gel permeation chromatography, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Their lower critical solution temperature was tuned near physiological temperature by adjusting the hydrophilic-to-hydrophobic monomer ratio. PGE-incorporated LNPs prepared by rapid vortex mixing showed uniform particle sizes, low polydispersity, high mRNA encapsulation efficiency, and good colloidal stability. Temperature-dependent changes in hydrodynamic diameter and polydispersity were monitored by dynamic light scattering to determine the apparent phase-transition temperature. The PGE composition was designed to maintain a hydrophilic, stealth-like surface at 37 °C and reduce surface shielding near 40 °C, thereby promoting cellular interaction. Cytotoxicity, cellular uptake, and mRNA delivery efficiency were evaluated in A549 and RAW 264.7 cells and compared with conventional PEG-LNPs. Cy5-labeled mRNA was also used to assess temperature-dependent cellular uptake. These findings demonstrate the potential of thermoresponsive PGE-LNPs as a safe, efficient, and temperature-responsive PEG-alternative platform for mRNA delivery.