Optimizing Peptide-Conjugated Lipid Nanoparticles for Efficient siRNA Delivery across the Blood-Brain Barrier and Treatment of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a WHO grade 4 glioma and the most common malignant primary brain tumor. Addressing the clinical management of GBM presents an exceptionally daunting and intricate challenge, particularly in overcoming the blood-brain barrier (BBB) to deliver effective therapies to the brain. Nanotechnology-based drug delivery systems have exhibited considerable promise in tackling this aggressive brain cancer. However, the BBB remains a key challenge in achieving effective brain delivery of nanocarriers. Here, we have optimized a lipid nanoparticle (LNP) formulation (C2) and modified the LNP with Angiopep-2 peptide, which exhibits the most significant improvements in blood-brain barrier penetration and brain accumulation (about 2.23% injection dose). Using the Ang-2-coupled C2 LNP formulation, we researched the therapeutic effect of Polo-like Kinase 1(PLK1)-targeted siRNA delivery to treat a mouse model of GBM. The optimized LNP formulation was demonstrated to significantly inhibit mouse GBM growth and extend the median survival of mice (2.18-fold). This work demonstrates the efficacy of a brain-targeted siRNA delivery system in GBM treatment. As the understanding of the role of RNAs in GBM deepens and innovative delivery methods are continually developed and refined, RNA-based therapies could emerge as a crucial breakthrough in the advancement of brain tumor treatment.