Esterase-triggered morphology and charge variable lipid nanoparticles enhance mRNA delivery and synergistically boost immune response

Lipid nanoparticles (LNPs) have shown vast potential for mRNA therapies as non-viral nucleic acid delivery systems. However, efficient delivery of mRNA into cells remains a significant challenge for LNPs because of the difficulty in endosome escape efficiency. Herein, we developed a novel esterase (ES) −activated structure and charge variable ionizable lipid (EIL) and prepared EIL-LNPs to deal with this issue. Once the EIL was hydrolyzed, it triggered a range of morphology and charge variation within the EIL-LNPs, leading to the endosomal escape of mRNA. Compared to MC3-LNPs, EIL-LNPs were able to mediate at least a 1.5-fold enhancement of mRNA expression efficiency in vitro and 3.2-fold in vivo . Mechanism studies revealed that EIL promoted the cellular internalization and endosomal escape of mRNA, particularly EIL C18 . In addition, EIL-LNPs elicited maturation of DCs. OVA mRNA@EIL C18 -LNPs increased CD8 + T cells infiltrating within the tumors and induced anti-tumor cytokine secretion, enhancing the efficacy of immunotherapy against melanoma. In summary, the present study supported EIL C18 -LNPs were not only as a novel and promising ionizable lipids for efficient delivery of mRNA, but also as a potential adjuvant for synergistically boosting the immune response induced by mRNA-encoded antigens. It holds great promise for improving the efficacy of immunotherapy.