Journal of Controlled Release

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 selfassemble 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