Smart microenvironment-activatable silybin nano-prodrug for precise NIR-II fluorescence monitoring and on-demand therapy of acute liver injury.

Acute liver injury (ALI) is a serious disease characterized by liver function impairment caused by multiple causes in a short period of time. Due to lack of precise diagnosis and timely intervention, many patients with ALI rapidly progress to liver dysfunction and liver failure. Here, a multifunctional silybin nano-prodrug, PTS@IR, was developed that integrated microenvironment-activatable second near-infrared (NIR-II) fluorescence (FL) imaging for precise diagnosis and timely therapy of ALI. The PTS@IR was formed through the self-assembly of a reactive oxygen species (ROS)-cleavable thioketal (TK) linker that connected polyethylene glycol and the clinical hepatoprotective drug silybin, followed by encapsulation of the NIR-II fluorescent dye IR 1061. In in vitro oxidative stress cell models, PTS@IR restored the quenched NIR-II FL, significantly alleviated cellular oxidative damage, and inhibited cell apoptosis. After intravenous injection into liver ischemia-reperfusion injury (LIRI) and drug-induced liver injury (DILI) mouse models, the PTS@IR specifically lit up the site of liver injury via NIR-II FL imaging, enabling highly sensitive diagnosis and real-time therapeutic monitoring of ALI. Activated by excess ROS in the pathological microenvironment, the nano-prodrug underwent in situ degradation and released silybin for on-demand therapy. Timely dual antioxidant and anti-inflammatory effects and inhibition of ferroptosis through modulation of the Nrf2/GPX4 axis collectively alleviated ALI. Notably, the PTS@IR could be completely degraded into small molecules, effectively avoiding the potential metabolic burden and toxic side effects of conventional nanodrugs. Overall, the multifunctional nano-prodrug PTS@IR provides a secure and effective theranostic strategy for precise diagnosis and timely treatment of ROS-related diseases.