Reticuloendothelial system blockade does not enhance siRNA-LNP circulation or tumor accumulation in mice

One of the biggest challenges for siRNA-based therapeutics is intracellular delivery into the target cell, which can be facilitated by encapsulating siRNA in lipid nanoparticles (LNPs). In this study, we formulated D-Lin-MC3-DMA-LNPs encapsulating siRNA against the androgen receptor (AR), a key driver in prostate cancer. We effectively knocked down AR expression at both the mRNA as well as protein levels in vitro in AR-expressing prostate cancer cell lines. However, when moving to in vivo studies, siRNA-LNP efficacy is hindered by rapid clearance by the reticuloendothelial system (RES) in the liver and spleen. We evaluated whether transient RES blockade through systemic pre-administration of dextran sulfate or liposomes could extend the circulation time and enhance tumor accumulation of siRNA-LNPs in tumor-bearing mice. In two different mouse prostate cancer (PCa) xenograft models, we observed that, upon systemic administration, LNPs still predominantly accumulated in the liver and spleen, with only limited tumor uptake. Our findings demonstrate that pre-treatment with dextran sulfate or liposomes did not enhance siRNA-LNP blood circulation time or tumor accumulation in vivo, indicating the need for alternative strategies to enhance siRNA-LNP delivery to tumors.