Cholesterol surface-modified oncolytic adenovirus enriched with apolipoprotein E penetrates the blood-brain barrier to target glioblastoma immunotherapy.

Glioblastoma (GBM) remains a therapeutic challenge due to its aggressive behaviour and the limitation of drug delivery by the blood-brain barrier (BBB). Conventional oncolytic adenoviruses (OAs) suffer from poor targeting efficiency. To overcome this limitation, we developed a cholesterol-modified OA (OA@Cho). This engineered virus actively regulates protein corona formation in the bloodstream, selectively enriching apolipoprotein E (ApoE). By exploiting low-density lipoprotein receptor (LDLR)-mediated BBB transcytosis, OA@Cho achieves precise glioma targeting and enhances therapeutic delivery. Critically, upon reaching the GBM site, OA@Cho induces an anti-tumor immune response, turning "cold" tumors into "hot" tumors by inducing immunogenic cell death (ICD). The proposed "surface modification-ApoE enrichment-receptor-mediated" paradigm establishes a transformative platform that enables oncolytic viruses to bypass biological barriers, thereby advancing targeted viral therapies against CNS malignancies with high translational relevance.