Golden Vesicular Nanoadjuvant-Loaded Injectable Hydrogel for Locoregional Photothermal-Immunotherapy of Unresectable Glioblastoma.

Abstract

Glioblastoma (GBM) as the most malicious primary brain tumor is infiltrative and often unresectable, which coupled with a profoundly immunosuppressive tumor microenvironment (TME) lead to a poor prognosis for patients. Here, we developed a golden vesicular nanoadjuvant (Au/TLR3-V) comprising gold nanoclusters and TLR3 agonist poly(I:C), formulated within an injectable hydrogel (Au/TLR3-V@gel) for locoregional photothermal-immunotherapy of large orthotopic GBM. Upon near-infrared (NIR) irradiation, Au/TLR3-V generated a potent photothermal response that induced immunogenic cell death and promoted dendritic cell (DC) activation. In TME‑mimicking systems, Au/TLR3-V pre-treated GL261 cells activated DCs accompanied by the upregulation of T‑cell‑recruiting chemokines. In murine models of advanced orthotopic GBM, a single intratumoral injection of Au/TLR3-V@gel followed by a brief NIR irradiation orchestrated a two-stage therapeutic process: localized thermal ablation of the tumor bulk (physical reduction) and subsequent release of Au/TLR3-V to facilitate DCs' capture of tumor-derived antigens and subsequently amplify DC activation (biological sweeping). When combined with anti‑CTLA‑4 blockade, this therapy achieved an 33% complete cure rate and established potent systemic anti-GBM immunity. By transforming an unresectable and immunologically "cold" tumor into a locally confined immunogenic "hotspot" using a soft, brain-compliant depot, this work provides a promising locoregional approach for unresectable GBM. STATEMENT OF SIGNIFICANCE: The treatment of unresectable glioblastoma is limited by the lack of biomaterials that can simultaneously provide safe intracranial retention, local tumor ablation, and immune activation. This study presents a brain-mimetic injectable hydrogel incorporating a golden vesicular nanoadjuvant (Au/TLR3‑V@gel) for locoregional photothermal-immunotherapy. The hydrogel offers mechanical compliance with brain tissue and sustained retention, while the released nanoadjuvant amplifies dendritic cell activation in response to tumor antigens generated by photothermal ablation. By coupling local cytoreduction with immune remodeling and further combination with anti-CTLA-4 blockade, this platform achieves durable survival benefits in orthotopic glioblastoma. These findings establish a promising biomaterials-based strategy for intracranial immunotherapy of unresectable brain tumors.