Water-Stable Hydrazone-Linked Porous Organic Cage-Enhanced Nanoparticle Brachytherapy for the Treatment of Glioblastoma

Radiotherapy has played a crucial role in the treatment of glioblastoma (GBM). Continuous advancements have aimed to maximize radiation delivery to tumor regions while minimizing injury to the surrounding healthy tissues. Recently, local brachytherapy has emerged as a promising approach for GBM. In this study, we developed a water-stable hydrazone-linked porous organic cage (HPOC-101) material, which possesses eight O-N-O chelation sites capable of efficiently coordinating with ¹⁷⁷Lu, and can be administered via stereotactic injection to enhance brachytherapy for GBM. HPOC-101 (abbreviated as Cage) enables rapid, efficient, and stable radiolabeling with clinically established radionuclides, including ⁸⁹Zr and ¹⁷⁷Lu, even at room temperature. Following extensive grinding, smaller crystal grains can penetrate cells, thereby enhancing tumor cell-killing effects. In contrast, larger crystal grains can remain in intercellular spaces for prolonged periods, amplifying localized radiation effects. By delivering ¹⁷⁷Lu via local stereotactic injection, the cage enhances local brachytherapy and extends the duration of radionuclide activity in GBM mouse models. Intracellular ¹⁷⁷Lu-Cage complexes demonstrate increased efficacy in eliminating tumor cells. Furthermore, radionuclide-radiotherapy-induced immunogenic cell death (ICD) is also an important mechanism of internal radiotherapy. Our research shows that nanolabeled nuclides can activate local immune effects by accruing tumor infiltration of M1-like macrophages and recruiting CD8⁺ effector T cells. This study thus presents a highly effective and water-stable organic molecular cage system for radionuclide chelation in brachytherapy, offering a promising strategy for the localized treatment of glioblastoma.