Multitalented Hybrid Targeted Nanoconstructs Selectively Repress Survival Genes and Induce Breast Tumor Regression In Vivo.

Abstract

Dysregulation of survival genes is a significant factor in the development of breast cancer and other cancers. Transcriptional downregulation of these genes offers a promising therapeutic strategy for cancer treatment by inducing apoptosis. Reducing expressions of these genes by RNA interference-mediated silencing is a potential strategy for more effective gene suppression. The research developed a novel protamine biopolymer-modified GSH-responsive biodegradable mesoporous silica nanoparticle system to suppress MCL-1 and Survivin genes' transcriptional activity in MCF-7 tumor-bearing mice. The nanocarriers were characterized using techniques like DLS, XRD, FTIR, GSH-utilization, SEM, and TEM. The nanocarriers were tested for their ability to deliver siRNAs into target cells, and their toxic behavior was assessed in vitro and in vivo. The nanocarriers' gene silencing and anti-cancer efficacy were assessed in both in vitro and in vivo models. The study revealed that synthesized MUC1 aptamer-conjugated protamine-modified nanocarriers (MPPM) offer stability to siRNAs, target MCF-7 tumor, and induce apoptosis with dual siRNAs. Additionally, the MPPM nanocarrier demonstrated significant potential for targeting the MCF-7 tumor in the mice model, and the histological findings suggested its biosafety profile. The siMCL-1/siSur@MPPM nanocarriers demonstrated a significant anti-tumor effect in an in vivo mice model through the silencing of target genes and the induction of apoptosis. These results indicate that the biodegradable siMCL-1/siSur@MPPM nanocarrier provides a significant combination of targeted delivery, biodegradability, effective gene silencing, and reduced off-target effects, suggesting its potential as a promising nanomedicine for breast cancer treatment.