Peptide modified lipid nanoparticles Co-Delivering IL-12 mRNA and PD-L1 siRNA for glioblastoma immunotherapy.

Lipid nanoparticles (LNPs) have emerged as the most advanced nucleic acid delivery vehicles in clinical applications, achieving successful targeting of major organs such as the liver, spleen, and lungs. However, efficient penetration of the blood-brain barrier (BBB) continues to be a key obstacle for brain-targeted applications. In this study, we developed a peptide modified LNPs system for the co-delivery of IL-12 mRNA and PD-L1 siRNA to achieve combined immunotherapy against glioblastoma (GBM). This dual-nucleic-acid delivery strategy simultaneously activates pro-inflammatory immune responses and suppresses immune checkpoint pathways, thereby alleviated the highly suppressed GBM microenvironment. By comparing the in vivo biodistribution of LNPs modified with various peptides (RGD, AP2, RVG29, FA, and Tf), we found that RGD modified LNPs (RLNPs) exhibited the strongest luciferase signal in the brain, indicating superior BBB penetration. Overall, RLNPs demonstrated enhanced brain-targeting capability and improved immunotherapeutic efficacy, suggesting that this delivery strategy provides a promising platform for central nervous system therapeutics.