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

Apr 29, 2026International journal of pharmaceutics

Peptide-Enhanced Lipid Nanoparticles Delivering IL-12 mRNA and PD-L1 siRNA for Brain Tumor Immunotherapy

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Abstract

RGD modified lipid nanoparticles (RLNPs) showed the strongest brain penetration among various peptide modifications.

Lipid nanoparticles are recognized as advanced tools for delivering nucleic acids in clinical settings.
Efficient delivery to the brain is hindered by the blood-brain barrier.
RLNPs facilitate the co-delivery of IL-12 mRNA and PD-L1 siRNA for glioblastoma treatment.
This method activates immune responses while inhibiting immune checkpoint mechanisms.
In vivo studies indicated enhanced brain-targeting capability of RLNPs compared to other peptide modifications.

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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.