A rapid-response smart nanoplatform with dual T₁-T₂ activation for acidic microenvironment imaging

Acidity-activatable magnetic resonance imaging (MRI) nanoprobes offer great potential for in vivo cancer imaging by targeting the acidic tumor microenvironment (TME). However, their effectiveness is limited by the delayed response at tumor sites and uncontrollable background noise, compromising imaging accuracy and reliability. Herein, an acidic TME-responsive nanoprobe, SPIO@ZIF-8@Gd (SZG), with dually activatable T₁ and T₂ MR signals is shown for acidity-selective contrast enhancement in a rapid response manner. It shows decreased T₁ and T₂ contrast intensity in normal physiological conditions. Once targeting acidic TME, the zeolitic imidazolate framework-8 (ZIF-8) layer undergoes instantaneous decomposition, releasing Gd³⁺ (T₁-weighted), and exposing the inner SPIO (T₂-weighted) core, thereby sequentially recovering the signals. Compared to previously reported T₁-T₂ nanoprobes, SZG demonstrates noticeable “dual activation” after just 30 min and reaches its peak 4 h after acid incubation. Additionally, it shows an excellent “acidity correlation” between relaxation times and pH values. When the SZG nanoprobe is used combined with “dual-contrast enhanced subtraction (DESI)”, the contrast difference between diseased and normal tissue can be increased by 10 times, which is significantly higher than traditional single-mode T₁/T₂ contrast agents. Collectively, these findings demonstrate a rapid imaging strategy of dual-activation MR imaging of the acidic TME and simultaneous background suppression, thus paving the way for precise tumor malignancy differentiation, early tumor detection, and accurate tumor grading.