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

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.