Tailored Nanogel Network Topology Enables Clinical Ultrasound‐Induced Mechanochemical Activation for In Vivo Therapy

Polymer mechanochemistry enables the selective mechanophore activation for precise molecular release. However, this field has long relied on the strong cavitation effects of low‐frequency ultrasound, which are incompatible with clinically high‐frequency ultrasound (> 1 MHz), hindering its biomedical applications. Herein, we report a nanogel network topology‐programmed mechanochemical strategy, enabling iterative activation of mechanophores under high‐frequency (up to 2.4 MHz) and low‐intensity (down to 2 W/cm 2 ) ultrasound. By introducing network topology as a design parameter, we established the relationship between nanogel topology, ultrasound frequency, and mechanochemical activity, revealing that distinct network topologies selectively accumulate mechanical forces under different ultrasound frequencies. Meanwhile, the thermal effect of high‐frequency ultrasound lowers the activation barrier of mechanophores, further promoting their efficient activation. Remarkably, under high‐frequency ultrasound, nanogels achieve an activation rate of 12.6%/min, placing it among the most efficient activation systems reported to date. Importantly, combining nanogels with clinical low‐intensity focused ultrasound, we developed a new ultrasound‐mediated therapeutic paradigm—synergistic sonothermal and mechanochemical therapy, achieving complete elimination of advanced tumors with a single short treatment. This work establishes network topology engineering as a general strategy for programming mechanochemistry, and opens new opportunities for the in vivo biomedical applications of polymer mechanochemistry.