SOX9 siRNA Loaded Lipid Nanoparticles Actively Targeted: Formulation, Delivery, and Antitumor Effect on Colorectal Cancer In Vitro and In Vivo

Jul 28, 2025Molecular pharmaceutics

Lipid Nanoparticles Delivering SOX9 siRNA Target Colorectal Cancer Cells and Reduce Tumor Growth in Lab and Animal Tests

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Abstract

The optimized R-LNPs have a uniform particle size of 159.6 ± 0.93 nm and high encapsulation efficiency of 90.71 ± 1.63%.

R-LNPs are composed of specific lipids and a peptide for targeted delivery of SOX9 siRNA in colorectal cancer treatment.
R-LNPs demonstrated sustained release and good stability in serum conditions.
Efficient uptake of R-LNPs by HCT-116 cells occurred through various endocytic pathways.
R-LNPs loaded with siSOX9 inhibited proliferation, migration, and invasion of colorectal cancer cells.
In vivo studies showed that R-LNPs effectively reduced tumor growth in xenograft models.
The observed antitumor effects were linked to the silencing of SOX9 and the downregulation of oncogenic mediators.

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Small interfering RNA (siRNA)-based therapy, which silences disease-associated genes, has emerged as a potential therapeutic strategy for various disorders, including cancer. Lipid nanoparticles (LNPs) have become a leading platform for efficient siRNA delivery. SOX9, a family member of SRY-related high-mobility-group box (SOX) transcription factors, plays an important role in the pathogenesis and progression of colorectal cancer (CRC). Here, we developed cRGDfK peptide-modificed LNPs (R-LNPs) composed of DLin-MC3-DMA, DMG-PEG, DSPC, DSPE-PEG-cRGDfK, and cholesterol for the targeted delivery of SOX9 siRNA (siSOX9) in CRC treatment. The formulation, delivery, and antitumor effect on CRCandwere explored. The optimized R-LNPs exhibited favorable physicochemical properties including a uniform particle size (159.6 ± 0.93 nm), low polydispersity index (PDI = 0.207 ± 0.016), near-neutral zeta potential (2.74 ± 0.35 mV), and high encapsulated efficiency (90.71 ± 1.63%). Additionally, R-LNPs demonstrated sustained and controlledrelease and good serum stability. The prepared R-LNPs were efficiently uptaken by HCT-116 via clathrin, lipid rafts, and caveolae dependent endocytosis and macropinocytosis. Subsequently, R-LNPs were colocalized with lysosomes before escaping into the cytoplasm, ensuring effective siRNA release.distribution studies confirmed tumor-specific accumulation for R-LNPs in HCT-116 xenograft models. Functionally, R-LNPs loading siSOX9 inhibited the proliferation, migration, and invasion of HCT-116 cells and Caco-2 cells (< 0.05 or 0.01) and inhibited tumor growth and proliferation in tumor-bearing mice (< 0.05 or 0.01). The antitumor effects were attributed to the silence of SOX9, which subsequently downregulated key oncogenic mediators, including β-catenin, cyclin D1, and c-Myc (< 0.05 or 0.01). Furthermore, R-LNPs demonstrated favorable safety inapplication. In conclusion, our cRGDfK-modified LNPs loading siSOX9 represent a promising targeted therapeutic strategy for CRC, offering both efficacy and biocompatibility. in vitro in vivo in vitro In vivo P P P in vivo

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SOX9 siRNA Loaded Lipid Nanoparticles Actively Targeted: Formulation, Delivery, and Antitumor Effect on Colorectal Cancer In Vitro and In Vivo

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