Targeted dual degradation of GPC-3 and VEGFR with multivalent DNA nanoflower-based LYTACs for hepatocellular carcinoma therapy.

While targeted therapies for hepatocellular carcinoma (HCC) have advanced, their clinical benefits remain constrained by limited efficacy, off-target toxicity, and the frequent emergence of drug resistance and recurrence. To address these challenges, we developed a multivalent DNA nanoflower-based dual-targeting LYTAC (lysosome-targeting chimera) platform tailored for HCC. This NanoLYTAC integrates two key functional elements: (i) a high-density array of bispecific aptamers that simultaneously recognize glypican-3 (GPC-3)-a highly HCC-specific surface marker-and vascular endothelial growth factor receptor (VEGFR), and (ii) galactose (Gal) modifications that enable liver-specific targeting via the asialoglycoprotein receptor (ASGPR). The construct is preferentially internalized by HCC cells, where it promotes the ASGPR-mediated lysosomal degradation of both VEGFR and GPC-3, leading to potent suppression of cell proliferation and migration, and induction of apoptotic death. In vivo, the NanoLYTAC exhibits pronounced tumor-specific accumulation and achieves significant tumor growth inhibition without inducing detectable systemic toxicity. Together, this work establishes a targeted, efficient, and well-tolerated dual-protein degradation strategy, offering a promising therapeutic avenue for HCC.