Aluminum-Based Metal−Organic Framework Nanoplatform Combines Chemo-Nanotherapy in an Intrahepatic Walker 256 Rat Tumor Model: Association with Glycerophospholipid Metabolic Changes

Abstract Hepatocellular carcinoma (HCC) treatment is severely limited by the low efficacy and drug resistance of current monotherapies. While nanocarriers for sorafenib (Sor) delivery have been explored, platforms that combine multimodal therapy and elucidate deep-seated anti-tumor mechanisms remain lacking. To address this, we engineered a nanosystem by loading Sor onto an aluminum-based metal−organic framework (Sor@Al-MOF), which combines chemotherapy with the intrinsic bioactivity of the nanocarrier. Sor@Al-MOF nanoparticles exhibited a well-defined lamellar structure, with a zeta potential of 10.10 ± 0.69 mV. Sor@Al-MOF achieved a high drug loading content (56.43% ± 0.36%) and encapsulation efficiency (77.38% ± 4.20%), and exhibited a cumulative release of 65.74 ± 0.55% at pH 5.3 after 72 h. In vitro, Sor@Al-MOF showed potent cytotoxicity against human HCC HepG2 cells (IC50 = 88.40 ± 0.12 μg/mL). In an intrahepatic Walker 256 rat tumor model, Sor@Al-MOF demonstrated enhanced therapeutic efficacy. Integrated metabolomics provided preliminary insights into potential metabolic changes in this model, including changes in choline kinase α (CHKα)-related glycerophospholipid metabolism. This study presents Sor@Al-MOF as a promising combinatorial nanotherapeutic candidate and offers a foundational basis for exploring metabolism-targeting strategies in liver cancer treatment.