Fe3+-responsive aggregable gold nanoplatform enables siRNA-mediated chemoresistance reversal and combined photothermal-temozolomide therapy for glioblastoma.

Glioblastoma (GBM) remains highly lethal, and standard temozolomide (TMZ) therapy is undermined by O6-methylguanine-DNA-methyltransferase (MGMT)-driven resistance. Herein, we present a Fe3+-responsive aggregable gold nanoplatform (siMGMT@P-T D-Q Au NP) for systemic delivery of MGMT-targeting siRNA (siMGMT) and enables on-demand photothermal therapy (PTT). The platform reconciles the size-performance trade-off of siMGMT@P-T D-Q Au NP: it preserves a small hydrodynamic size during circulation to promote blood-brain barrier (BBB) penetration and tumor access. When in the tumor microenvironment, Fe3+-induced siMGMT@P-T D-Q Au NP rapid aggregation promotes plasmonic coupling, red-shifts near-infrared absorption, and markedly amplifies 808-nm photothermal ablation. Concurrently, Furin triggers siMGMT release to suppress MGMT and resensitize tumor cells to TMZ. The proposed sequential regimen comprises intravenous administration of siMGMT@P-T D-Q Au NP, Fe3+-triggered siMGMT@P-T D-Q Au NP aggregation to enhance PTT to kill tumors, and subsequent oral TMZ as maintenance therapy. This strategy integrates gene silencing to reverse chemoresistance, Fe3+-responsive aggregable enhancement of PTT, and standard-of-care chemotherapy, addressing key delivery barriers while aiming to improve therapeutic breadth with minimal invasiveness. STATEMENT OF SIGNIFICANCE: Our research covers the following highlights: 1. The constructed size-adaptive Au NP first crosses the blood-brain barrier as small particles and then accumulates as larger ones to enhance therapy. 2. The enhanced photothermal conversion efficiency of Au NP enables synergistic photothermal therapy against glioma. 3. Downregulation of drug-resistance gene MGMT maximizes the therapeutic efficacy of temozolomide. 4. The combined strategy of gene silencing and photothermal-chemotherapy achieves enhanced glioma treatment. Over all, this platform represents an innovative size-adaptive gold nanoplatform that achieves siRNA-mediated reversal of TMZ chemoresistance and enables synergistic photothermal therapy against glioblastoma, offering a paradigm for the future development of integrated, multimodal glioma treatment.