Brain-targeted polymersomes mediating RNAi of STAT3 sensitize glioblastoma to temozolomide and immunotherapy

Glioblastoma (GBM) is among the most aggressive brain tumors, presenting significant therapeutic challenges due to intrinsic and acquired resistance to treatment, alongside a highly immunosuppressive tumor microenvironment (TME). While temozolomide (TMZ) is the standard chemotherapeutic agent with the ability to penetrate the blood–brain barrier (BBB), its clinical efficacy is often limited. Here, we report a strategy employing Apolipoprotein E (ApoE) peptide-functionalized polymersomes loaded with small interfering RNA (siRNA) targeting signal transducer and activator of transcription 3 (Apstat3) to amplify the anti-GBM effects of TMZ and immunotherapy. Apstat3 demonstrated small, uniform particle sizes, stability in siRNA encapsulation, and effective downregulation of STAT3 and O⁶-methylguanine-DNA methyltransferase (MGMT) in GL261 cells, sensitizing these tumor cells to TMZ. The combinatorial approach not only significantly inhibited GBM cell proliferation, migration and invasion but also improved dendritic cells (DCs) maturation under TME-mimicking environment. In orthotopic GL261 mouse models, intravenous injection of Apstat3 co-administered with oral TMZ resulted in a twofold increase in median survival and reshaped the TME. Notably, combined treatment with anti-CTLA4 therapy tripled median survival to 64 days, achieving complete remission observed in 20% of the mice. This siSTAT3 delivery strategy holds promise for enhancing GBM treatment outcomes.