Elastin-like peptides for efficient and safe delivery of mRNA

mRNA vaccines represent a significant advancement in the field of cancer treatment and prevention. Nevertheless, challenges persist in optimizing mRNA transfection efficiency and mitigating associated side effects. In this study, we have developed a genetically engineered modular elastin-like peptide (ELP), designated V₂₀K₄₀L. The V₂₀ module is hydrophobic, while K₄₀ is hydrophilic and highly positively charged. These modules self-assemble with Melan-A mRNA (M) and CpG (C) to form nanocomposites (MC@V₂₀K₄₀L). Due to the inverse transition cycling effect, MC@V₂₀K₄₀L transitions from a loose to a tight conformation in response to physiological temperature (37 °C), enhancing its stability. The nanocomposites exhibit multiple cellular entry pathways, including endocytosis and macropinocytosis, thereby improving cellular uptake efficiency. Moreover, under the synergistic effect of the KALA peptide (L) and K₄₀, MC@V₂₀K₄₀L efficiently escapes lysosomes and translates more antigens, thereby boosting antigen delivery and immune memory. Compared to DOTAP/mRNA lipoplexes (MC@DOTAP), MC@V₂₀K₄₀L demonstrates a 400 % increase in mRNA transfection efficiency, with a concomitant reduction in inflammatory responses. These genetically engineered ELPs promote efficient delivery of mRNA, increase transfection efficiency, and also mitigate side effects, offering great translational potential for mRNA vaccines.