Nanoparticles hijack intracellular glucose for sustained boron trapping in cancer cells.

Boron neutron capture therapy (BNCT) requires selective accumulation and retention of 10B in cancer cells during neutron irradiation. However, current clinical boron agents are limited by transient intracellular residence, rapid clearance, and insufficient tumour selectivity. Here, we report a glucose-hijacking strategy that converts the glucose avidity of malignant cells into an endogenous chemical machinery for sustained boron trapping. We engineered AbChol10B, an albumin-based nanoparticle containing a 10B-labeled cholesterol derivative, Chol10B. Upon internalization, Chol10B is released and spontaneously covalently conjugates with intracellular glucose. This in situ process creates a bulky complex that anchors 10B within the cells, while simultaneously engaging glucose to disrupt tumour metabolic homeostasis. Driven by the increased glucose uptake of malignant cells, this reversible covalent binding becomes more pronounced, thereby promoting prolonged 10B retention. Compared with boronophenylalanine (10BPA), AbChol10B increased 10B uptake by 238.8-fold and reduced 10B clearance by 81.96%. GLUT1 knockdown markedly reduced this retention, supporting a glucose-dependent mechanism. In vivo, AbChol10B increased intratumoural 10B accumulation by 33.52-fold and achieved a tumour to blood ratio (T/B) of 24.48. Most notably, even at a sub-threshold macroscopic tumour boron concentration (∼7.7 ppm), this boron trapping strategy suppressed tumour growth by 87.32% with minimal systemic toxicity. These findings suggest that intracellular boron trapping mediated by hijacking glucose can enhance the effective utilization of boron and reframes BNCT drug design from maximizing bulk tumour boron loading to engineering intracellular boron residence.