Versatile Nano-PROTAC-Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapeutics

Background:

• Overexpression of bromodomain-containing protein 4 (BRD4) is linked to poor lung cancer prognosis.
• BRD4 suppression induces apoptosis and tumor shrinkage in lung cancers.
• Proteolysis targeting chimera (PROTAC) technology offers precise protein degradation for therapy.

Purpose of the Study:

• To develop a versatile nano-PROTAC system for targeted lung cancer therapy.
• To investigate the efficacy of a novel nano-PROTAC (CREATE) in degrading BRD4 in lung cancer cells and tumor-associated macrophages (TAMs).
• To evaluate the therapeutic potential of CREATE in preclinical lung cancer models.

Main Methods:

• Fabrication of CREATE nanoparticles using pH/GSH-responsive DS-PLGA to encapsulate dBET6 (BRD4-targeted PROTAC).
• Camouflage of nanoparticles with engineered lung cancer cell membranes for dual targeting of cancer cells and TAMs.
• Assessment of nanoparticle-induced apoptosis, tumor growth inhibition in subcutaneous and orthotopic mouse models, and tumor microenvironment modulation.

Main Results:

• CREATE nanoparticles demonstrated dual targeting of lung cancer cells and TAMs.
• The pH/GSH-responsive design facilitated efficient payload release and induced apoptosis in both cell types.
• Synergistic inhibition of tumor growth was observed in both subcutaneous and orthotopic models.
• CREATE treatment remodeled the tumor microenvironment through the elimination of cancer cells and TAMs.

Conclusions:

• The developed CREATE nano-PROTAC system effectively eliminates both lung cancer cells and TAMs.
• This dual-targeting strategy shows significant potential for remodeling the tumor microenvironment and enhancing lung cancer therapy.
• CREATE represents a promising new therapeutic avenue for efficient lung cancer treatment using PROTAC technology.