Catcher in the rel: Nanoparticles-antibody conjugate as NF-κB nuclear translocation blocker

Area of Science:

• Biochemistry
• Molecular Biology
• Nanotechnology

Background:

• Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor complex (p65/p50) regulates gene expression and is implicated in cancer.
• Directly targeting NF-κB proteins is a proposed cancer therapy strategy due to pathway crosstalk and compensation issues.
• The NF-κB inhibitor IκBα sequesters the p65/p50 complex in the cytoplasm.

Purpose of the Study:

• To develop and evaluate a nanoparticle-antibody system for directly blocking NF-κB p65 translocation to the nucleus.
• To investigate the therapeutic efficacy of this targeted approach in a preclinical cancer model.

Main Methods:

• Mesoporous silica nanoparticles (MSN) conjugated with TAT peptide for cell membrane transduction and perinuclear accumulation.
• p65-specific antibody on MSN to target and bind active NF-κB p65 in the perinuclear region.
• Assessment of nanoparticle size-exclusion blocking of nuclear translocation and combination therapy with doxorubicin in 4T1 tumor-bearing mice.

Main Results:

• The nanoparticle-antibody complex successfully targeted and trapped NF-κB p65 in the perinuclear region, preventing nuclear entry due to size exclusion.
• Combined treatment with the hybrid MSN and doxorubicin demonstrated significant therapeutic effects in mice with 4T1 tumors.
• The approach showed effective blocking of NF-κB p65 translocation near the nuclear pore.

Conclusions:

• Antibody-conjugated nanoparticles offer a novel strategy for targeting transcription factors by "nucleus focusing" and "size exclusion blocking."
• This method provides a generalizable platform for cancer therapy by directly inhibiting key oncogenic transcription factors.
• The developed nanoparticle system holds potential for modulating other transcription factors involved in various diseases.