Targeted Co-Delivery of Curcumin and Astragaloside IV via Hybrid Membrane-Coated Biomimetic Liposomes for Enhanced Lung Cancer Therapy.

Background: Lung cancer is the malignant tumor with the highest incidence and lethality worldwide. Existing therapeutic modalities suffer from side effects, drug resistance, and limited efficacy, and there is an urgent need to develop safer and more effective therapeutic strategies. Curcumin (Cur) and astragaloside IV (AS) are promising natural anti-cancer agents. However, their poor aqueous solubility and low bioavailability limit their clinical efficacy. Natural cell membrane-based biomimetic drug delivery platform provides an effective strategy for efficient and targeted co-administration. Methods: The optimal synergistic ratio of Cur and AS against lung cancer cells was determined using the Combination Index (CI) method. Dual-drug-loaded liposomes were prepared via the thin-film hydration method and subsequently coated with a hybrid membrane derived from cancer cells and erythrocytes to form biomimetic liposomes (CM@AC lip). These nanoparticles were characterized for size, charge, stability, and drug release. Their targeting, endocytosis mechanism, antitumor efficacy, and biosafety were evaluated in vitro and in vivo. Results: The CM@AC liposomes exhibited a uniform spherical structure with a synergistic ratio of 1.5:1 for AS and Cur. The liposomes had a particle size of 111.86 ± 4.12 nm, a Zeta potential of -20.8 ± 3.63 mV, and encapsulation efficiencies of 63.81 ± 1.22% for Cur and 60.38 ± 0.89% for AS, respectively. The liposomes demonstrated excellent stability. Cellular and animal studies confirmed its superior tumor-targeting ability and immune evasion. CM@AC lip significantly enhanced cytotoxicity, apoptosis, and invasion inhibition against Lewis lung carcinoma cells compared to single-drug treatments. In vivo, it achieved a high tumor inhibition rate (74.59 ± 17.52%) without inducing significant systemic toxicity. Conclusion: The hybrid membrane-coated biomimetic liposome effectively co-delivers Cur and AS-IV, demonstrating enhanced antitumor efficacy and favorable biosafety via synergistic action, improved targeting, and immune evasion. This strategy presents a promising platform for lung cancer combination therapy.