Inhalable Polymeric PROTAC Nanococktail for Targeted Protein Degradation in Idiopathic Pulmonary Fibrosis

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Pulmonary Medicine

Background:

• Idiopathic pulmonary fibrosis (IPF) involves a pathological circuit of epithelial senescence and fibroblast activation, leading to lung damage.
• Current proteolysis-targeting chimeras (PROTACs) face challenges in pulmonary delivery and efficacy for fibrotic lung diseases.

Purpose of the Study:

• To develop an inhalable, enzyme-activated polymeric PROTAC nanococktail for concurrent degradation of two key profibrotic signaling regulators in fibrotic lungs.
• To overcome limitations in pulmonary delivery and enhance therapeutic intervention in IPF.

Main Methods:

• Designed a nanococktail with two nanoparticles: GAL@SD (releases STING-degrading PROTACs activated by senescence-associated β-galactosidase) and FAP@BD (releases BRD4-degrading PROTACs activated by fibroblast activation protein-α).
• Evaluated nanoparticle mucus penetration, pulmonary retention, and accumulation in fibrotic lesions.
• Assessed therapeutic efficacy in a bleomycin-induced mouse model of pulmonary fibrosis.

Main Results:

• The dual-PROTAC nanococktail demonstrated efficient mucus penetration, improved pulmonary retention, and targeted accumulation in fibrotic lung lesions.
• Inhalation of the nanococktail led to localized degradation of STING and BRD4.
• Achieved superior therapeutic efficacy compared to single PROTAC nanoparticles, restoring lung architecture, improving respiratory function, and reducing collagen deposition.

Conclusions:

• An inhaled dual-PROTAC nanotherapeutic strategy effectively targets both epithelial senescence-associated inflammation and fibroblast-driven matrix remodeling in pulmonary fibrosis.
• This approach shows significant potential for treating fibrotic lung diseases by simultaneously addressing key pathological drivers.