Recent Advances in Mesoporous Silica Nanoparticles Delivering siRNA for Cancer Treatment

Abstract

Silencing genes using small interfering (si) RNA is a promising strategy for treating cancer. However, the curative effect of siRNA is severely constrained by low serum stability and cell membrane permeability. Therefore, improving the delivery efficiency of siRNA for cancer treatment is a research hotspot. Recently, mesoporous silica nanoparticles (MSNs) have emerged as bright delivery vehicles for nucleic acid drugs. A comprehensive understanding of the design of MSN-based vectors is crucial for the application of siRNA in cancer therapy. We discuss several surface-functionalized MSNs' advancements as effective siRNA delivery vehicles in this paper. The advantages of using MSNs for siRNA loading regarding considerations of different shapes, various options for surface functionalization, and customizable pore sizes are highlighted. We discuss the recent investigations into strategies that efficiently improve cellular uptake, facilitate endosomal escape, and promote cargo dissociation from the MSNs for enhanced intracellular siRNA delivery. Also, particular attention was paid to the exciting progress made by combining RNAi with other therapies to improve cancer therapeutic outcomes.

Keywords: RNAi therapeutics; cancer treatment; gene therapy; mesoporous silica nanoparticles; siRNA delivery.

Figure 1

Mechanisms of small interfering (si)-RNA-loaded mesoporous silica nanoparticles (MSNs) after modification.

Figure 2

MSN-based active-targeting delivery and responsive release of siRNA for cancer RNA interference (RNAi) therapeutics.

Figure 3

The mechanism of endosomal escape of MSNs.

Figure 4

Loaded and tumor-targeted delivery of siRNAs via MSNs for overcoming drug resistance. (A) Schematic representation of the synthesis of MSNP-PLR-PEG(OCH3) and overcoming resistance through the BCl-2/BCl-xL pathway; (B) schematic illustration of the preparation process and antagonistic drug-resistance strategies of siRNA-MSN@PVA NPs; (C) structural evolution of MSNs from small pore-sized MSNs to large pore-sized MSNs, the hierarchical MSNs in present work for gene/drug codelivery for MDR reversing, and the schematic illustration of the formation mechanism of MSNs@MONs; (D) schematic of siRNA-MSNs nanoconstruct synthesis; (E) schematic illustration of synthesis steps and MSNs functionalization to obtain NH2-MSN, NH2-MSN-siRNA, and NH2-MSN-siRNA-chitosan functionalized with PEG-folate and PEG-TAT; (F) the preparation of folic-acid-conjugated mesoporous silica nanoparticles loaded with myricetin and MRP-1 siRNA.

Figure 5

Promotion of apoptosis in tumor cells by MSNs-loaded siRNAs. (A) Scheme of the preparation process of Vorinostat and cFLIP siRNA-coloaded mesoporous silica nanoparticles with pH-ultrasensitive valves (Vor/siR@MSN-PB-PEG) for suppression of cFLIP in cancer cells, Vor/siR@MSN-PB-PEG-inhibited cFLIP expression, and induced apoptosis caspase pathways in cancer cells; (B) EGFR-targeted (cetuximab) mesoporous silica nanoparticle (NP) platform for PLK1 siRNA (siPLK1) delivery or C-siPLK1-NP and proapoptotic effects of C-siPLK1-NP treatment on NSCLC (A549, H460) cell lines. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns = not statistically significant.

Figure 6

Effective activation of immunity by MSNs loaded with siRNAs. (A) Preparation and intracellular behavior of c(RGDfK)-MSN; (B) schematic and TEM images of O/siRNA/pD (Nanosac) preparation and antitumor activity of Nanosac in Balb/c mice bearing CT26 tumors; (C) schematic and TEM images of siSTAT3-CpG-NP and its TEM electron micrographs. Effectiveness of siSTAT3–CpG–NP in inducing in situ tumor vaccination in mice bearing bilateral syngeneic melanoma tumors. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

Figure 7

Combining multiple therapies against tumors through MSN delivery of siRNAs. (A) Preparation of FePt nanoparticles and siRNA coloaded mesoporous silica nanoplatform sSFP and enhanced ferroptosis process of tumor cells by Cys depletion; (B) schematic illustration of light-triggered RNA delivery by tumor-penetrating iMSNs for siPlk1/miR-200c combination therapy.