A biomimetic phase-separating hydrogel potentiates local chemo-virotherapy to eradicate recurrent glioblastoma

  • J Control Release. 2026 Jul 10:395:114990. doi: 10.1016/j.jconrel.2026.114990.
Yajie Hu  1 ,  Shiyan Nong  2 ,  Zhiwei Zeng  2 ,  Yinqiu Tan  3 ,  Xiang Fang  4 ,  Wenjing Zhong  2 ,  Zhaoyang Wang  5 ,  Xiaofeng Sui  6 ,  Hongbo Zhang  7 ,  Qi Liu  8 ,  Cuifeng Wang  9 ,  Hongchao Xu  10
Affiliations
  • 1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Department of Neurosurgery, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518101, PR China.
  • 2. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
  • 3. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China.
  • 4. Hangzhou Bisheng Biomaterials Co., Ltd., No. 267 Kejiyuan Road, Hangzhou, Zhejiang 310000, PR China.
  • 5. Department of Neurosurgery, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518101, PR China.
  • 6. School of Chemistry and Chemical Engineering, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi 330013, PR China; Jiangxi Engineering Laboratory of Waterborne Coating, School of Chemistry and Chemical Engineering, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi 330013, PR China.
  • 7. Department of neurosurgery, The second affiliated hospital of Nanchang University, No 1. Mingde Road, Nanchang, Jiang Xi 330002, PR China. Electronic address: [email protected].
  • 8. The First Dongguan Affiliated Hospital Guangdong Medical University No. 42, Jiaoping Road Dongguan, Guangdong 523710, PR China. Electronic address: [email protected].
  • 9. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: [email protected].
  • 10. Department of Neurosurgery, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518101, PR China. Electronic address: [email protected].
PMID: 42097225 DOI: 10.1016/j.jconrel.2026.114990
Abstract

Combining local oncolytic virotherapy with chemotherapy offers a logical strategy to prevent glioblastoma (GBM) recurrence, yet physical and biological incompatibilities between viruses and drugs restrict their co-administration. Here, inspired by viral liquid-liquid phase separation (LLPS), we developed a biomimetic phase-separating hydrogel (PSgel) that enables the spatially segregated and sustained co-delivery of oncolytic herpes simplex virus 2 (HSV-2) and the multi-kinase inhibitor sorafenib. Mechanistically, the chemo-viral combination cooperatively depletes the repressive histone MARK H3K27me3, reversing the epigenetic resistance. Furthermore, this combination synergistically remodels the immunosuppressive tumor microenvironment, characterized by recruiting CD8+ T cells and Iba-1+ microglia. In a clinically relevant post-surgical GBM murine model, we demonstrate that PSgel-mediated co-delivery of HSV-2 and sorafenib effectively suppresses tumor recurrence and significantly extends overall survival. These findings establish biomimetic phase separation as a structural solution to resolve drug-virus incompatibilities, overcome epigenetic resistance, and potentiate local chemo-virotherapy for the eradication of recurrent GBM.

Keywords
Epigenetic regulation; Hydrogel; Oncolytic virus; Phase-separating; Post-surgical recurrence; Sorafenib.
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