Glycosylated dendrimer nanoamplifiers hijack DNA damage‐immune crosstalk for enhanced dual‐track therapy of orthotopic glioblastoma

Abstract Synergistic radiotherapy‐immunotherapy in glioblastoma (GBM) faces dual tumor resistance mediated by enhanced DNA damage repair and programmed cell death‐ligand 1 (PD‐L1) upregulation. Herein, we engineer a glycosylated dendrimer nanoamplifier (Gal‐G5(Au)‐DMC) that hijacks the DNA damage‐immune crosstalk for enhanced radiotherapy‐immunotherapy of orthotopic GBM. The Gal‐G5(Au)‐DMC was constructed by modifying demethylcantharidin (DMC) to glycosylated fifth‐generation (G5) polyamidoamine dendrimers pre‐encapsulated with 2.0 nm gold nanoparticles (Au NPs). The modification with DMC enhanced the stability of Gal‐G5(Au)‐DMC in the systemic circulation, while the galactose ensured its optimal blood‐brain barrier penetration and tumor accumulation. In the tumor microenvironment, the pH‐responsive release of DMC amplifies Au NPs‐mediated radiosensitization via DNA repair suppression and reverses immunosuppression by reducing the protein phosphatase 2A activity of T cell population. When combined with anti‐PD‐L1 antibody, the synergy between radiosensitization‐induced immunogenic cell death and DMC‐driven immunomodulation increased the proportion of cytotoxic and regulatory T cell populations, achieving a 50% long‐term survival rate in orthotopic GBM models even at day 50—twice the efficacy of conventional radio‐immunotherapy. This nanoamplifier intervene in the interaction between DNA damage and the immune system, blocking repair‐mediated resistance while converting radiation‐induced stress signals into sustained anti‐tumor immunity. Synchronizing these dual tracks yields a clinically actionable paradigm for GBM therapy.