On-Demand Detaching Nanosystem for the Spatiotemporal Control of Cancer Theranostics

Engineering multiple theranostic modalities into a single nanoscale entity holds great potential to rejuvenate cancer treatments; however, enabling the sophisticated spatiotemporal control of each component for maximizing theranostic improvement and minimizing side effects concurrently remains a challenge. Herein, an intelligent detachable "nanorocket" is developed to sequentially manipulate and optimize multitheranostic processes for magnetic resonance-assisted ultrasound-drug combined therapy (MR-HIFU-Drug). The "nanorocket" is constructed by integrating multicomponent (MnCO₃, doxorubicin, silica) on the pH-sensitive CaCO₃ nanoparticles step by step via cation exchange and controlled heterogeneous nucleation, in which doxorubicin is encapsulated in both carbonates and silica component. The "nanorocket" can initiate sequential detachment in the acidic tumor microenvironment. Specifically, carbonates decompose instantly, releasing Mn²⁺ as the MR contrast agent and leaving hollow silica nanostructure behind as the HIFU synergistic agent. Consequently, burst release of drug is also triggered, further triggering the degradation of silica, which in turn regulates the slow release of drug from the silica matrix. Thus, efficient tumor inhibition is achieved by enhanced HIFU ablation and biphase release of doxorubicin with a stepwise clearance of Mn and Si. This work establishes a system for the systematic spatiotemporal dispatch of diverse theranostic components for the balance of efficacy and safety in cancer theranostics.