Targeted delivery of siRNA against sodium-dependent phosphate co-transporter 2b (NPT2b) via functionalized mesoporous silica nanocarriers suppresses breast cancer cell growth

The sodium-dependent phosphate co-transporter 2b (NPT2b) plays an important role in maintaining phosphate homeostasis. In previous studies, we reported that high dietary inorganic phosphate consumption could increase NPT2b expression in mice while knockdown of NPT2b expression has been shown to reduce tumorigenesis. NPT2b has been found to be highly expressed in human breast cancer tissues. The correlation between elevated NPT2b expression in the breast tissue and poor prognosis in oncogenic breast diseases led us to investigate whether knockdown of NPT2b could regulate breast cancer growth. To address this issue, breast cancer cells were transfected by small interfering RNA (siRNA) directed against NPT2b (siNPT2b), complexed with a mesoporous silica nanoparticle (MSN) grafted with polyethyleneimine (PEI) and modified with folic acid as a nonviral vector (hereafter, functionalized MSN). We used two distinct PEI molecular weights (10 and 25 kDa) to optimize the balance between nucleic acid delivery efficiency and cytotoxicity of cationic modified MSN. In this study, we developed an effective nanocarrier to deliver siRNA into breast cancer cells. Our findings demonstrated that functionalized MSN effectively targeted the folate receptor and delivered siNPT2b, resulting in the downregulation of NPT2b expression, possibly through regulation of phosphate consumption. Our results strongly indicate that siNPT2b delivery through our engineered nanocarrier especially when grafted with 10 kDa PEI can influence breast cancer growth and offers valuable insights into the development of nonviral nanocarriers for siRNA delivery, potentially contributing to the advancement of targeted cancer therapy.