A Polymer–Lipid Nanosystem Comprising siRNA and Gemcitabine for Pancreatic Cancer Treatment

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor that is typically diagnosed at an advanced stage and is characterized by a high metastatic rate and resistance to many therapeutic drugs. Conventional single-drug treatment strategies often prove ineffective because of the intricate tumor microenvironment and poorly understood pathological mechanisms. Recently, immunotherapy and gene therapy have emerged as promising treatments with significant potential. In this study, we engineered and tested a C–X–C motif chemokine receptor 4 (CXCR4) inhibitory polymer–lipid complex nanoparticle system (∼88.6 nm) designed to deliver siRRM2 (a small interfering RNA targeting RRM2 encoding ribonucleotide reductase regulatory subunit M2). This system could enhance the therapeutic effect of gemcitabine in a metastatic pancreatic cancer orthotopic model. In both in vitro and in vivo models, the nanoparticle delivery system, composed of lipid nanoparticle-polymeric Plerixafor (PAMD)/siRRM2, in conjunction with gemcitabine, exhibited significant enhancement in the therapeutic efficacy with a notable synergistic effect. In pancreatic cancer cells, the triple combination achieved 85% cell death, and a 74% reduction in tumor volume in orthotopic PDAC mice (mean tumor weight: 0.19 g vs 0.74 g in untreated controls, p < 0.0001, n = 6). Additionally, the nanoparticle delivery system could modulate the immune microenvironment within tumors. In summary, the present project achieved multitargeting through the codelivery of a nanosystem and drug combination, thereby reducing the likelihood of chemotherapy drug resistance, inhibiting tumor metastasis and growth, and improving the survival rate of patients with pancreatic cancer. This approach is expected to provide an effective strategy to treat refractory pancreatic cancer.