Enhanced tumor penetration across the blood-brain barrier: endoplasmic reticulum membrane hybrid siRNA nanoplexes

The penetration of nanocarriers across the blood-brain barrier (BBB) through transcellular transcytosis is difficult owing to their lysosomal degradation after endocytosis. This obstacle prevents the targeted delivery of siRNAs in the treatment of glioma or other brain diseases. In this study, endoplasmic reticulum (ER) membranes derived from glioma cells were used to fabricate the integrative hybrid nanoplexes (EhCv/siRNA NPs) for enhancing the penetration efficiency of crossing BBB through transcytosis. Compared to undecorated Cv/siRNA NPs, the ER membrane-decorated EhCv/siRNA NPs evaded lysosomal degradation through a non-degradable endosome-Golgi/ER pathway, resulting in a significantly stronger ability to cross the BBB through transcellular transcytosis and better gene-silencing effects of siRNAs in U87 glioma in vitro and in vivo. Altogether, this study is valuable for designing the optimized non-degradable transcellular transcytosis across the blood-brain barrier and advancing drug delivery to brain.