A Phototherapy Nanosensitizer-Unlocked Multihit Strategy to Inhibit Tumor Stemness and Potentiate Sorafenib Response in Hepatocellular Carcinoma

Tumor stemness, possessing self-renewal capabilities and high tumor-initiating potential, is one of the determinants of resilience against sorafenib for hepatocellular carcinoma (HCC). In this regard, a facile construction of the multityrosine kinase inhibitor sorafenib conjugated with black phosphorus nanosheets was demonstrated (denoted as BPS), which integrated multiple and distinctive properties, including effective stemness inhibition, mitochondria metabolic disruption, ferroptosis amplification, sorafenib resistance reversal, and outstanding photothermal conversion efficiency. Both <i>in vitro</i> and <i>in vivo</i> analyses collectively demonstrated that the proposed nanoplatform exhibited remarkable potential for synergistic photodynamic-photothermal therapies. Besides, the BPS-mediated tumor-associated macrophage epigenetic repolarization was highly beneficial for relieving immunosuppression and overcoming sorafenib resistance. Such a comprehensive structure optimization strategy provides a cooperative tumor stemness suppression-sorafenib resistance disarming approach for the treatment of HCC.