Biguanide‑modified ursolic acid as a multifunctional lipid‑mimetic carrier of DOX liposome for synergistic chemotherapy.

Doxorubicin (DOX) therapy is constrained by limited tumor accumulation, inefficient intracellular delivery, and dose-dependent systemic toxicity. Ursolic acid can potentiate DOX activity, but its poor compatibility with liposomal assembly complicates stable co-loading. We synthesized a biguanide-modified UA derivative (UAB) as an amphiphilic lipid-mimetic component and fabricated hyaluronic acid (HA)-modified liposomes co-encapsulating DOX and UAB (HA-DOX@UAB Lips). The optimized formulation showed high encapsulation efficiencies for both agents, a uniform nanoscale size distribution, and pH-dependent DOX release. In BGC-823 gastric cancer cells, HA-DOX@UAB Lips produced the highest intracellular DOX-associated fluorescence, synergistic cytotoxicity, the greatest inhibition of clonogenic growth and wound closure, and the strongest apoptosis-associated response among the tested formulations. In H22 hepatocellular carcinoma-bearing mice used as a non-gastric proof-of-concept model, HA-DOX@UAB Lips produced the greatest tumor suppression without overt short-term organ injury. These findings support UAB as a multifunctional lipid-mimetic component and bioactive partner for DOX co-delivery. Further studies in dedicated gastric cancer models and receptor-specific experiments are required to establish gastric-cancer-specific efficacy and the contribution of CD44 to cellular uptake.