Microfluidic lipid nanoparticles co-delivering siMOB1A and paclitaxel for ovarian cancer therapy

Ovarian cancer is the foremost cause of mortality among gynecologic malignancies. Paclitaxel (PTX) exerts a significant therapeutic effect on ovarian cancer by targeting microtubules and impeding the cell cycle progression during the mitosis phase. MOB kinase activator 1 A (MOB1A) has been proven to regulate the cycle progression of ovarian cancer cells. Utilizing small interfering RNA (siRNA) to target MOB1A (siMOB1A) displays efficiency in blocking the cycle progression during the interphase of mitosis. The combined application of paclitaxel and siMOB1A holds promise in halting the cell cycle progression in ovarian cancer cells across different phases. Lipid nanoparticles delivering siMOB1A and paclitaxel (SPLNPs) were prepared by microfluidic technology. Then, the size distribution, zeta potential, morphology, and size stability of SPLNPs were characterized. Confocal laser scanning microscopy and flow cytometry were used to detect the cellular uptake ability of SPLNPs. RT-qPCR and Western blot were performed to evaluate the knockdown effect on MOB1A mRNA and protein levels. CCK-8 and colony formation assay were performed to evaluate the cytotoxicity of SPLNPs. A wound-healing assay was performed to detect the effect on cell migration. Flow cytometry was used to assess the effects on the cell cycle and apoptosis. Tumor-bearing mouse models were constructed to detect the distribution, anti-tumor effect, and biosafety in vivo. SPLNPs exhibited spherical morphology with an average diameter of approximately 113.5 nm and were efficiently internalized by ovarian cancer cells. The drug loading content was 7.50% for siMOB1A and 2.07% for paclitaxel. Through the RNA interference (RNAi) mechanisms facilitated by SPLNPs, effective suppression of MOB1A expression in ovarian cancer was achieved at both mRNA and protein levels. The knockdown efficiency reached 66.2% at the siMOB1A dose of 5 nM. Then, enhanced apoptosis of ovarian cancer cells was observed, accompanied by cell cycle modulation. Compared to siMOB1A and paclitaxel, SPLNPs showed superior cytotoxicity and effectively curbed the migration and proliferation ability of ovarian cancer cells. Additionally, in vivo experiments demonstrated that SPLNPs inhibit tumor growth, achieving an inhibition rate of approximately 65.23%. SPLNPs enabled the co-delivery of siMOB1A and PTX, resulting in enhanced antitumor activity and providing a promising co-delivery platform for ovarian cancer therapy.