A dual-targeted, pH-sensitive cationic liposomal system co-delivering paclitaxel and siCXCR2 for synergistic inhibition of lung cancer cells in vitro

Lung cancer remains the most commonly diagnosed malignancy and a leading cause of cancer-related mortality worldwide. Paclitaxel (PTX), a first-line chemotherapeutic agent for advanced non-small cell lung cancer (NSCLC), is frequently compromised by acquired drug resistance. Here, through network pharmacology analysis and experimental validation, we identified CXCR2 as a key regulator of PTX resistance. Based on this finding, we developed a pH-sensitive cationic liposomal system for co-delivery of PTX and CXCR2-targeting siRNA (siCXCR2). In contrast to traditional liposomes, which suffer from several drawbacks—poor stability, susceptibility to phospholipid oxidation and hydrolysis, inconsistent targeting efficiency, and a tendency to accumulate in the liver and kidneys—the liposomes developed herein exhibit moderate particle size, high physiological stability, and effective protection of siRNA against nuclease degradation. Surface modification with YSA and SS31 targeting peptides further enhanced cellular uptake and intracellular delivery. In vitro experiments demonstrated that the liposomes achieved a CXCR2 mRNA silencing efficiency of nearly 50%. In the A549 cell line, the mean apoptosis rates for the HA/siCXCR2/PTX, HA/siNC/PTX and PTX monotherapy groups were 35.1%, 23.4% and 14.4%, respectively. This suggests that liposomes loaded with siCXCR2 sensitize A549 cells to PTX and enhance PTX-induced apoptosis. Overall, this study has established a novel YSA/SS31 dual-targeted pH-sensitive cationic liposome platform to enable the co-delivery of PTX and siCXCR2, providing an in vitro intervention strategy with broad prospects for overcoming chemoresistance in lung cancer and improving treatment outcomes. Furthermore, this system effectively reversed chemoresistance and enhanced cytotoxicity, contributing to synergistic anti-tumor effects. However, it should be noted that this study is currently limited to in vitro validation and requires further in vivo experiments and preclinical evaluation.