Ionizable mesoporous silica nanoparticle-mediated siAURKB delivery for colorectal cancer therapy

Abstract

Colorectal cancer (CRC) is a common malignant tumor with high incidence and mortality worldwide. Conventional therapeutic strategies, such as surgical resection and chemotherapy, which result in improved outcomes for some patients, are greatly hindered by drug resistance and off-target toxicity. Small interfering RNA (siRNA)-mediated RNA interference has provided a breakthrough for precision CRC therapy. However, efficient delivery of siRNA to the tumor site with its complex tumor microenvironment remains challenging. Here, an ionizable mesoporous silica nanoparticle (MSN)-based nanocarrier with high siRNA loading capacity and enhanced cell membrane penetration capability is developed for effective CRC therapy. By modifying diethylamino groups onto the surface of MSNs featuring maze-like pores, a new siRNA delivery carrier, denoted as MPMNC, is successfully prepared. MPMNC exhibits improved cellular uptake efficiency in CT26 cells and a significant fluorescence silencing effect in EGFP-293T cells. Furthermore, aurora-B siRNA (siAURKB), which downregulates the expression of AURKB in tumor cells to induce apoptosis, is loaded onto MPMNC to afford the nanomedicine siAURKB@MPMNC, which delivers siAURKB to tumor cells and inhibits tumor growth effectively (tumor growth inhibition rate of 64.9%) through intratumor injection in CRC model mice. Additionally, it exhibits excellent biocompatibility in vitro and in vivo. Overall, this work presents a novel nanomedicine, siAURKB-loaded MSN, highlighting its surface modification with ionizable amino groups, which offers a promising therapeutic paradigm for CRC.