Fine‐Tuning Lipid‐Coated Porous Silicon Nanoparticles for siRNA Delivery

Small interfering RNA (siRNA) is a growing treatment avenue for cancer patients. However, formulating siRNA to achieve high tumoral delivery efficiency is challenging. Among various formulation strategies, porous silicon nanoparticles (pSiNPs) are unique due to the versatile nanoengineering options. This study builds on and aims to further refine two successful strategies previously developed for pSiNPs-based siRNA delivery systems: calcium silicate sealing and lipid coating. The application of alternative lipid composition based on ionisable lipids (dilinoleyl-methyl-4-dimethylaminobutyrate (MC3)) is investigated and head-to-head compared with previously developed coatings based on quaternary ammonium lipids (1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)) associated with potential in vivo safety concerns. While the MC3 formulation underperforms compared to the DOTAP-based formulation in terms of siRNA loading and in vitro cellular association, comparable lysosomal escape rate and acceptable levels of siRNA transfection are observed. In vivo biodistribution of formulations is compared head-to-head, with higher tumor accumulation observed for the MC3 formulation in an orthotopic breast cancer murine model. Formulations are well-tolerated at a 20 mg/kg dose. As another approach for refinement of the formulation for siRNA delivery, the lipid-coated pSiNPs are functionalized using an anti-human desmoglein-2 monoclonal antibody (aDSG2) to achieve better transfection efficacy.