The siEGFR nanoplexes for the enhanced brain glioma treatment: Endoplasmic reticulum biomimetic strategy to induce homing effect and non-degradable intracellular transport

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The epidermal growth factor receptor (EGFR) plays a pivotal role in tumor progression and is an essential therapeutic target for treating malignant gliomas. Small interfering RNA (siRNA) has the potential to selectively degrade EGFR mRNA, yet its clinical utilization is impeded by various challenges, such as inefficient targeting and limited escape from lysosomes. Our research introduces polyethylene glycol (PEG) and endoplasmic reticulum membrane-coated siEGFR nanoplexes (PEhCv/siEGFR NPs) as an innovative approach to brain glioma therapy by overcoming several obstacles: 1) Tumor-derived endoplasmic reticulum membrane modifications provide a homing effect, facilitating targeted accumulation and cellular uptake; 2) Endoplasmic reticulum membrane proteins mediate a non-degradable "endosome-Golgi-endoplasmic reticulum" transport pathway, circumventing lysosomal degradation. These nanoplexes demonstrated significantly enhanced siEGFR gene silencing in both in vitro and in vivo U87 glioma models. The findings of this study pave the way for the advanced design and effective application of nucleic acid-based therapeutic nanocarriers. Formation and administration of PEhCv/siRNA NPs. A) The PEhCv/siRNA NPs were synthesized by incorporating U87 cancer-derived EM and DSPE-PEG 2000 into Cv/siRNA NPs via membrane integration. B) Following intravenous administration, PEhCv/siRNA NPs localized within heterotopic glioma tumors and were internalized by cancer cells. They were then transported through a 'non-degradable' intracellular route involving endosomes and the Golgi/ER, bypassing the endosome-lysosome pathway. This route enabled the nanoparticles to escape lysosomal degradation within the cell, thereby potentiating their gene-silencing efficacy against brain glioma tumors. • Polyethylene glycol and endoplasmic reticulum membrane-coated siEGFR nanoplexes-for brain glioma therapy. • A non-degradable "endosome-Golgi-Endoplasmic reticulum" transport pathway to evade the lysosomal degradation. • siEGFR downregulate EGFR protein to inhibit the growth of brain glioma.