Stimuli-Responsive Peptide/siRNA Nanoparticles as a Radiation Sensitizer for Glioblastoma Treatment by Co-Inhibiting RELA/P65 and EGFR

Abstract

Bohong Cen,1,2 Jian Zhang,1 Xinghua Pan,3 Zhongyuan Xu,2 Rong Li,1 Chengcong Chen,1 Baiyao Wang,1 Zhiyong Li,4 Guoqian Zhang,1 Aimin Ji,5 Yawei Yuan1 1Department of Radiation Oncology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510095, People’s Republic of China; 2Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, Guangdong, 510515, People’s Republic of China; 4Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 5Department of Pharmacy, The Seventh Affiliated Hospital of Southern Medical University, Foshan, Guangdong, 528244, People’s Republic of ChinaCorrespondence: Yawei Yuan; Aimin Ji, Email [email protected]; [email protected]: To develop a novel approach for increasing radiosensitivity in glioblastoma (GBM) by using targeted nanoparticles to deliver siRNA aimed at silencing the EGFR and RELA/P65 genes, which are implicated in radioresistance.Patients and Methods: We engineered biodegradable, tumor-targeted, self-assembled, and stimuli-responsive peptide nanoparticles for efficient siRNA delivery. We evaluated the nanoparticles’ ability to induce gene silencing and enhance DNA damage under radiation in vitro and in vivo. The nanoparticles were designed to exhibit pH-responsive endosomal escape and αvβ 3 integrin targeting, allowing for preferential accumulation at tumor sites and traversal of the blood-brain tumor barrier.Results: The application of these nanoparticles resulted in significant gene silencing, increased apoptosis, and decreased cell viability. The treatment impaired DNA repair mechanisms, thereby enhancing radiosensitivity in GBM cells. In a GBM mouse model, the combination of nanoparticle treatment with radiotherapy notably prolonged survival without apparent toxicity.Conclusion: Our findings suggest that nanoparticle-mediated dual gene silencing can effectively overcome GBM radioresistance. This strategy has the potential to improve clinical outcomes in GBM treatment, proposing a promising therapeutic avenue for this challenging malignancy.Keywords: glioblastoma, siRNA delivery, self-assembly nanoparticles, radiation sensitizer

Keywords

• glioblastoma
• sirna delivery
• self-assembly nanoparticles
• radiation sensitizer