Polymer-locking fusogenic liposomes for glioblastoma-targeted siRNA delivery and CRISPR–Cas gene editing
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence l'intérêt de liposomes fusogènes pouvant traverser la barrière hémato-encéphalique (BHE) et délivrer de courts ARNs interférents ou le système d'édition génomique CRISPR–Cas9
In patients with glioblastoma (GBM), upregulated midkine (MDK) limits the survival benefits conferred by temozolomide (TMZ). RNA interference (RNAi) and CRISPR–Cas9 gene editing technology are attractive approaches for regulating MDK expression. However, delivering these biologics to GBM tissue is challenging. Here we demonstrate a polymer-locking fusogenic liposome (Plofsome) that can be transported across the blood–brain barrier (BBB) and deliver short interfering RNA or CRISPR–Cas9 ribonucleoprotein complexes into the cytoplasm of GBM cells. Plofsome is designed by integrating a ‘lock’ into the fusogenic liposome using a traceless reactive oxygen species (ROS)-cleavable linker so that fusion occurs only after crossing the BBB and entering the GBM tissue with high ROS levels. Our results showed that MDK suppression by Plofsomes significantly reduced TMZ resistance and inhibited GBM growth in orthotopic brain tumour models. Importantly, Plofsomes are effective only at tumour sites and not in normal tissues, which improves the safety of combined RNAi and CRISPR–Cas9 therapeutics.
Nature Nanotechnology , résumé, 2024