Trivalent GalNAc-Mediated Delivery of Cucurbitacin B Overcomes Systemic Toxicity for Potent HCC Chemoradiotherapy.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, with limited therapeutic options. Cucurbitacin B (CuB) demonstrates potent anti-HCC activity but suffers from systemic toxicity and poor pharmacokinetics. To address these challenges, we developed a series of asialoglycoprotein receptor (ASGPR)-targeted small molecule-drug conjugates (SMDCs) for the precision delivery of CuB. The trivalent conjugate SMDC 23 exhibited efficient ASGPR-mediated cellular uptake and controlled drug release. It induced both autophagy and immunogenic cell death, triggered ROS-mediated DNA damage, activated the DNA damage response, and arrested the cell cycle, consequently enhancing the radiosensitivity of HCC cells. In HepG2-derived models, SMDC 23 achieved superior tumor accumulation, suppressed tumor growth by 76% at 30 mg/kg, and synergized with low-dose radiotherapy (2 Gy) to achieve 98% tumor inhibition, all with no observable systemic toxicity. This ASGPR-targeted CuB platform, particularly in combination with radiotherapy, represents a promising precision chemoradiotherapy strategy for HCC.