Study on Synergistic Treatment of Pancreatic Cancer by Multiple Small Interfering Ribonucleic Acid Lipid Nanoparticles of Disk Domain Receptor 1, Transforming Growth Factor β1, Tumor-Associated Calcium Signal Transduction Protein 2, and Polyligand Pr

Background/Objective: This study aimed to use multiple disk domain receptor 1 (DDR1), transforming growth factor β1 (TGFβ-1), tumor-associated calcium signal transduction protein 2 (TACSTD2), and polyligand proteoglycan 1 (SDC1) siRNA to treat pancreatic cancer with the goals of high specificity, significant therapeutic efficacy, and relatively low toxicity. Methods: (1) A microfluidic method was used to prepare siRNA-LNPs with different formulations. (2) Quantitative PCR (qPCR) and Western blot assays were used to detect the inhibitory effect of different-prescription siRNA-LNP formulations on mRNA and protein expression levels of related genes in PaTu 8988 pancreatic cells. (3) The anti-pancreatic cancer effect of multiple siRNAs combined with LNPs in vivo was evaluated using the BALB/c nude mouse model with subcutaneous pancreatic cancer xenografts. Results: (1) Three siRNA-LNP formulations, DMG, CE 1.5, and CE 0.75, were successfully prepared, exhibiting small particle sizes and uniform distribution. (2) qPCR and Western blot results indicated that DDR1, TGFβ-1, TACSTD2, and SDC1 siRNA-LNP significantly inhibited related genes’ mRNA and protein expression in pancreatic cancer PaTu 8988 cells. (3) Efficacy studies in animals indicated that multiple siRNA combined with LNPs in each group exhibited significant antitumor effects on pancreatic cancer tumor-bearing nude mice. The therapeutic efficacy of the combined siRNAs was superior to that of single siRNA treatments, indicating a clear combined effect, especially with three- and four-siRNA combinations. Conclusions: The prepared DDR1/TGFβ-1/TACSTD2/SDC1 siRNA-loaded LNP demonstrated a small particle size, high gene inhibition efficiency, and a significant therapeutic effect in treating pancreatic cancer. Its safety is generally acceptable, but attention should be paid to the toxicity caused by LNP excipients, especially cationic lipids.