Metformin-conjugated radiopaque nanogels with RF-triggered phase transition for programmable embolization and PD-L1 degradation

Transcatheter arterial chemoembolization (TACE) is widely used for hepatocellular carcinoma (HCC), yet its efficacy is frequently undermined by hypoxia-driven neovascularization and the consequent immune evasion that fuels recurrence. To overcome these limitations, we developed LM@ p Met 20 , a metformin-based upper critical solution temperature-type embolic agent loaded with liquid metal. Upon injection, LM@ p Met 20 underwent an initial sol-to-gel transition to occlude tumor vessels. Subsequent radiofrequency (RF) heating triggered a reversible gel-to-sol transition, allowing image-guided redistribution of the embolus to occlude neovessels. After RF cessation, LM@ p Met 20 re-gelled at physiological temperature, achieving on-demand, repeatable embolization within a single session to block both primary and collateral vessels. Furthermore, RF irradiation induced reactive oxygen species (ROS) generation from LM@ p Met 20 , contributing to direct tumor cytotoxicity. As a bioactive metformin-based system, LM@ p Met 20 metabolically reprogrammed the immune microenvironment by activating the AMPK pathway to degrade PD-L1, thereby reversing TACE-induced immune evasion. This effect synergized with anti-CTLA-4 immunotherapy to effectively suppress tumor metastasis and recurrence. Therefore, this bioactive platform integrates programmable embolization, RF-augmented dynamic therapy, and immune checkpoint-sensitizing immunotherapy in a single session, offering a promising strategy to overcome TACE resistance and improve HCC outcomes.