Dual‐Mechanism mRNA Delivery via Fluorinated‐Sorbitol Polyplexes: Enhancing Cellular Uptake and Endosomal Escape for COVID‐19 Vaccination

Abstract Advancements in mRNA delivery nanoparticles have significantly improved the potential for treating challenging diseases. Due to the inherent immunogenicity and rapid degradation of mRNA, specialized nanoparticles are required for efficient intracellular uptake, endosomal escape, and protection from lysosomal degradation. Although current methods enable transgene expression but achieving a balance between efficiency and toxicity remains challenging. In this study, an effective mRNA delivery system is developed by modifying a cationic polymer with sorbitol and fluorine, resulting in fluorinated polyethyleneimine with sorbitol functionalization (PFS). This polyplex enhances mRNA delivery through improved cellular uptake via sorbitol channels and caveolae‐mediated endocytosis, while fluorination facilitates endosomal escape and mitigates toxicity. The formulation demonstrated successful expression of Gaussian luciferase mRNA in both Raw 264.7 cells and Balb/c mice. Additionally, intramuscular administration of the SARS‐CoV‐2 spike mRNA vaccine elicited robust immune responses comparable to Moderna's LNP formulation. The vaccine effectively neutralized the Wuhan variant strain of SARS‐CoV‐2, as shown by PRNT 50 testing. These findings suggest that the PFS formulation is a promising candidate for developing polymeric mRNA vaccines targeting various infectious and non‐infectious diseases.