Structure-to-Therapeutic Transformation of Nanohydrogels Triggers Calcium Overload for Potentiated Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) holds immense promise for invasive tumors like melanoma. However, clinical translation is severely impeded by the challenge of achieving high, precise intratumoral boron accumulation. Herein, we developed a stimuli-responsive nanohydrogel, SA-Ca@(PAH-BA-PAH), designed for an "inject-and-trigger" strategy. The nanohydrogel features a calcium alginate core stabilized by layer-by-layer assembly of a boron drug (boric acid, BA) and polyelectrolyte PAH, serving as both a boron reservoir and a calcium source. Upon intratumoral administration, the nanohydrogel is stably retained until a subsequent local injection of EDTA triggers rapid calcium alginate core disassembly. This induces a synchronous burst release of boron agents and calcium ions, transforming the structural cross-linker Ca²⁺ into a therapeutic agent. This "structure-to-toxin" transformation generates a localized calcium overload that disrupts mitochondrial function and elevates reactive oxygen species (ROS), thereby sensitizing tumor cells to BNCT. <i>In vivo</i> studies demonstrated a tumor boron concentration of 83.38 ± 2.98 μg/g in melanoma-bearing mice─quadruple the clinical threshold. The synergy between BNCT and calcium interference therapy (CIT) achieved potent tumor ablation and elicited a robust antitumor immune response. Benefiting from precise intratumoral injection and localized triggering, this platform achieves a potent synergistic therapy for accessible solid tumors while circumventing systemic toxicity.