Molecular pharmaceuticsOct 22, 2026

Using Stronger Fat-Based Nanoparticles to Lower PD-L1 Levels in Breast Cancer Cells

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 23, 2026

Abstract

Systemic administration of a targeted solid lipid nanoparticle delivering CRISPR/Cas9 significantly inhibited tumor growth and metastasis in a mouse model of triple-negative breast cancer.

The targeted solid lipid nanoparticle system effectively downregulated programmed death ligand 1 (PD-L1), enhancing the immune response against cancer cells.
In vitro experiments showed that the nanoparticle system achieved higher transfection efficiency and PD-L1 knockdown in breast cancer cells compared to non-targeted controls.
Administration of the nanoparticle system led to increased T cell infiltration within the tumor environment in the mouse model.
The targeted approach demonstrated a favorable short-term safety profile, with no organ toxicity observed during the treatment period.
Results indicated that this method may offer a more effective alternative to standard chemotherapy in treating triple-negative breast cancer.

Simplified

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by the absence of targetable receptors and limited therapeutic options. Its inherently low immunogenicity necessitates strategies to enhance its susceptibility to immune attack. This study aimed to enhance the antitumor immune response by inducing downregulation of the programmed death ligand 1 (PD-L1), thereby increasing cancer cell recognition and activating tumor-specific immunity. To this end, a targeted solid lipid nanoparticle (tSLN) system was developed for the precise delivery of CRISPR/Cas9 plasmids to achieve functional PD-L1 downregulation. The SLN formulation comprised a cetyl palmitate core stabilized with cationic and PEGylated lipids. Functionalization with the tumor-penetrating peptide iRGD yielded tSLN, which demonstrated good colloidal stability, serum protection of the CRISPR cargo, and minimal cytotoxicity. In vitro studies in two breast cancer subtypes, the luminal MCF-7 and the triple-negative 4T1 line, confirmed greater transfection efficiency and PD-L1 knockdown by tSLN:Crispr/PD-L1 relative to non-targeted controls. In an orthotopic 4T1 mouse model, systemic administration of tSLN:Crispr/PD-L1 significantly inhibited tumor growth and metastasis while enhancing T cell infiltration, and was more effective than standard chemotherapy (paclitaxel) in this model. The targeted approach also exhibited a favorable short-term safety profile, with no organ toxicity detected over the treatment period. These findings underscore the potential of SLN-mediated CRISPR delivery as an immunomodulatory strategy for breast cancer, and particularly for TNBC.

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Using Stronger Fat-Based Nanoparticles to Lower PD-L1 Levels in Breast Cancer Cells

Abstract

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