Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted siRNA Delivery to HER2⁺ Breast Cancer

TLDR

In vivo delivery of siRNAs to inhibit disease‑relevant genes remains a key biomedical challenge. The study introduces a nanoparticle designed to extend siRNA half‑life, improve tumor uptake, and maximize knockdown efficacy. The construct consists of a 47‑nm mesoporous silica core coated with crosslinked polyethyleneimine–polyethylene glycol, loaded with HER2‑targeting siRNA and trastuzumab, and is amenable to scalable, reproducible production. In HER2‑positive models, the nanoparticles induced apoptosis, reduced HER2 protein by 60% in resistant xenografts, and, with repeated IV dosing, significantly suppressed tumor growth while showing a favorable safety profile, indicating readiness for clinical testing.

Abstract

In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. A new nanoparticle construct that is engineered for efficient delivery of siRNA to tumors is now described. The construct comprises a 47‐nm mesoporous silica nanoparticle core coated with a crosslinked polyethyleneimine–polyethyleneglycol copolymer, carrying siRNA against the human epidermal growth factor receptor type 2 (HER2) oncogene, and coupled to the anti‐HER2 monoclonal antibody (trastuzumab). The construct is engineered to increase siRNA blood half‐life, enhance tumor‐specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti‐HER2 nanoparticles produce apoptotic death in HER2 positive (HER2 + ) breast cancer cells grown in vitro, but not in HER2 negative (HER2 − ) cells. One dose of the siHER2–nanoparticles reduces HER2 protein levels by 60% in trastuzumab‐resistant HCC1954 xenografts. Administration of multiple intravenous doses over 3 weeks significantly inhibits tumor growth ( p < 0.004). The siHER2‐nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch‐to‐batch reproducibility and the production methods are suitable for large‐scale production. These results suggest that this siHER2‐nanoparticle is ready for clinical evaluation.