Inhalable Degradation-Tunable Hybrid Nanoparticles With Rapid Lysosomal Escape for Dual siRNA Therapy Against NSCLC

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Gene Therapy

Background:

• Gene therapy for lung cancer faces challenges with tumor targeting, penetration, and vector stability/toxicity.
• Conventional lipid-based vectors are unstable during nebulization and can be toxic due to high positive surface charge.

Purpose of the Study:

• To engineer inhalable hybrid nanoparticles (HNPs) for improved lung cancer gene therapy.
• To enhance nebulization stability, pulmonary delivery, tumor penetration, and transfection efficiency.
• To develop a dual siRNA strategy for synergistic therapeutic effects.

Main Methods:

• Developed rigid polyester shell-lipid core hybrid nanoparticles (HNPs) for pulmonary delivery.
• Systematically screened polyester shell types and molecular weights for optimal properties.
• Employed a dual siRNA approach targeting the TGF-β pathway and mutant KRAS.
• Utilized microfluidics for scalable manufacturing and tested inhalability with commercial nebulizers.

Main Results:

• HNPs demonstrated enhanced nebulization stability, pulmonary deposition, and mucus/tumor penetration.
• Achieved rapid endo/lysosomal escape, improving transfection efficiency in lung cancer cells and fibroblasts.
• Dual siRNA delivery led to significant tumor growth suppression and reduced metastasis.
• Microfluidics enabled scalable manufacturing compatible with commercial nebulizers.

Conclusions:

• Engineered HNPs offer a promising strategy for effective lung cancer gene therapy via inhalation.
• The dual siRNA approach combined with HNPs amplifies therapeutic efficacy against non-small cell lung cancer (NSCLC).
• HNPs show potential for clinical translation due to scalable manufacturing and nebulizer compatibility.