Combination Therapeutic Effect of Asiatic Acid & Curcumin-Loaded Liposomes Modified by Neutrophil Extracellular Traps for the Treatment of Oral Squamous Cell Carcinoma

Background: Tumor metastasis has been proven to represent the predominant cause of cancer-related mortality; therefore, the strategies simultaneously eradicating primary lesions and blocking dissemination cascades hold revolutionary potential in curative oral squamous cell carcinoma (OSCC) therapy. Methods: In this study, we designed novel neutrophil extracellular traps (NETs)-coating liposomes (CUR@AA-NLIP) for co-delivery of curcumin (CUR) and asiatic acid (AA), in which the introduction of NETs was expected to improve tumor-targeting ability, and the combination of CUR and AA was used to synergistically inhibit tumor development. Results: The characteristics analysis showed that CUR@AA-NLIP exhibited uniform size, phospholipid bilayer structure, and sustained drug release. In vitro studies demonstrated that CUR@AA-NLIP enhanced tumor cell uptake and macrophage escape, inhibited fibroblast activation and vessel tube formation, showing enhanced anti-proliferation and anti-migration capacities. In vivo results confirmed that CUR@AA-NLIP increased drug accumulation in the tumor region, showed enhanced anti-tumor efficacy (> 80% tumor suppression), and reduced lung metastasis. Conclusion: CUR@AA-NLIP holds great potentials in OSCC-targeting delivery of synergistic natural compounds and can achieve anti-proliferative and anti-metastatic effects by simultaneously enhancing tumor accumulation, reducing immune system clearance, and inhibiting of cancer-associated fibroblast (CAF) activation and angiogenesis, therefore exhibiting enhanced anti-OSCC efficacy.