Vasukutty Arathy, Chahal Sahil, Lee Kyung-Hwa, Park So-Hee, Kim Soo-Min, Shin Eunkyung, Kim You-Jin, Kim Dokeun, Lee Jung-Ah, Jeong Hye-Sook, Park In-Kyu
Department of Biomedical Sciences, Biomedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, 322 Seoyang-ro, Hwasun, 58128, Republic of Korea.
Department of Pathology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, 322 Seoyang-ro, Hwasun, 58128, Republic of Korea.
Adv Healthc Mater. 2025 Mar;14(6):e2403374. doi: 10.1002/adhm.202403374. Epub 2024 Dec 26.
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 testing. These findings suggest that the PFS formulation is a promising candidate for developing polymeric mRNA vaccines targeting various infectious and non-infectious diseases.
信使核糖核酸（mRNA）递送纳米颗粒的进展显著提高了治疗疑难疾病的潜力。由于mRNA固有的免疫原性和快速降解特性，需要专门的纳米颗粒来实现有效的细胞内摄取、内体逃逸以及防止溶酶体降解。尽管目前的方法能够实现转基因表达，但在效率和毒性之间取得平衡仍然具有挑战性。在本研究中，通过用山梨醇和氟对阳离子聚合物进行修饰，开发出一种有效的mRNA递送系统，得到了具有山梨醇功能化的氟化聚乙烯亚胺（PFS）。这种多聚体通过山梨醇通道和小窝介导的内吞作用改善细胞摄取，从而增强mRNA递送，而氟化则有助于内体逃逸并减轻毒性。该制剂在Raw 264.7细胞和Balb/c小鼠中均成功实现了高斯荧光素酶mRNA的表达。此外，肌肉注射严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突mRNA疫苗引发了与莫德纳公司的脂质纳米颗粒（LNP）制剂相当的强烈免疫反应。如空斑减少中和试验（PRNT）所示，该疫苗有效地中和了SARS-CoV-2的武汉变异株。这些发现表明，PFS制剂是开发针对各种感染性和非感染性疾病的聚合物mRNA疫苗的一个有前景的候选物。
