Surface-Confinement Effect Enables Bioorthogonal Drug Release in Tumors

A critical challenge in the bench-to-bedside translation of controlled drug release strategies is the sharp decline in reaction efficiency as biological complexity increases. A platform capable of maintaining bioorthogonal-like drug release─remaining minimally perturbed by physiological environments─would address an unmet clinical need. This is particularly relevant for radiotherapy-mediated drug release, where the oxidative activation of prodrugs is often compromised by the rapid quenching of reactive intermediates in vivo. Herein, we engineer a hafnium-based nanoscale metal-organic layer platform that leverages a unique "surface-confinement effect" to overcome this challenge. By covalently tethering prodrugs to the Hf-nMOLs surface, we constructed two-dimensional nanoreactors that spatially localize the activation process within an interface enriched with reactive species. This design effectively insulates the activation step from biological scavengers, ensuring efficient payload release efficiency across increasing biological complexity. When loaded with the topoisomerase I inhibitor Exatecan, the Hf-nMOLs system achieved an intratumoral drug-release G-value of 568 nM·Gy-1, resulting in potent radiosensitization and significant tumor-growth suppression under low-dose X-ray irradiation. This work presents a versatile strategy for robust radio-chemotherapeutic combinations, achieving the simultaneous release of diverse payloads activated by radiotherapy. Our findings also suggest that engineering nanoscale surface confinement may provide a generalizable materials strategy to help confer bioorthogonality to otherwise labile activation reactions.