Butyrate Modification Promotes Intestinal Absorption and Hepatic Cancer Cells Targeting of Ferroptosis Inducer Loaded Nanoparticle for Enhanced Hepatocellular Carcinoma Therapy.

Sorafenib is an oral-administered first-line drug for hepatocellular carcinoma (HCC) treatment. However, the therapeutic efficacy of sorafenib is relatively low. Here, an oral delivery platform that increases sorafenib uptake by HCC and induces potent ferroptosis is designed. This platform is butyrate-modified nanoparticles separately encapsulated with sorafenib and salinomycin. The multifunctional ligand butyrate interacts with monocarboxylate transporter 1 (MCT-1) to facilitate transcytosis. Specifically, MCT-1 is differentially expressed on the apical and basolateral sides of the intestine, highly expressed on the surface of HCC cells but lowly expressed on normal hepatocytes. After oral administration, this platform is revealed to boost transepithelial transport effectively and continuously in the intestine, drug accumulation in the liver, and HCC cell uptake. Following drug release in cancer cells, sorafenib depletes glutathione peroxidase 4 and glutathione, consequently initiating ferroptosis. Meanwhile, salinomycin enhances intracellular iron and lipid peroxidation, thereby accelerating ferroptosis. In vivo experiments performed on the orthotopic HCC model demonstrate that this combination strategy induces pronounced ferroptosis damage and ignites a robust systemic immune response, leading to the effective elimination of tumors and establishment of systemic immune memory. This work provides a proof-of-concept demonstration that an oral delivery strategy for ferroptosis inducers may be beneficial for HCC treatment.