Sulfur dioxide-releasing nanomotors improve the therapeutic effect of liver fibrosis by restoring the fenestrae of sinusoids.

The dual barriers formed by the capillarized liver sinusoids and excessive deposited extracellular matrix (ECM) significantly impede the retention of therapeutic agents in the fibrotic liver. Currently, there are limited reports on strategies capable of simultaneously overcoming these barriers. Here, we propose sulfur dioxide (SO2)-releasing nanomotors based on endogenous in vivo reactions to restore the fenestrae of sinusoids and degrade ECM by activating the endogenous signaling pathway to improve the retention of therapeutic agents in the damaged liver. These nanomotors leverage the specific enzyme concentration gradient in damaged liver tissue as a chemoattractant signal, guiding their targeted delivery. The nanomotors incorporate an l-cysteine-based substrate that, upon enzymatic catalysis, generates SO2. The released SO2 can upregulate the cyclic guanosine monophosphate expression to restore the fenestrated phenotype of liver sinusoidal endothelial cells. Concurrently, SO2 can stimulate the endogenous nitric oxide production to induce matrix metalloproteinase-1 activation to facilitate the collagen degradation. The animal experimental model also demonstrates the effective retention of nanomotors in damaged liver tissue and reversal of liver fibrosis.