Idiopathic pulmonary fibrosis (IPF) is sustained by a self-amplifying pathological circuit involving senescence-associated epithelial injury and fibroblast activation, which together drive persistent inflammatory signaling, excessive extracellular matrix deposition, and progressive loss of lung function. Although proteolysis-targeting chimeras (PROTACs) offer a powerful approach to eliminate disease-driving proteins, their application in fibrotic lung disease remains limited by inefficient pulmonary delivery, poor lesion retention, and insufficient intervention in multicellular profibrotic networks. Herein, we develop an inhalable enzyme-activated polymeric PROTAC nanococktail that enables concurrent degradation of two key profibrotic signaling regulators in fibrotic lungs. The nanococktail consists of GAL@SD and FAP@BD, two disease-microenvironment-responsive nanoparticles carrying distinct PROTAC cargos. GAL@SD responds to elevated senescence-associated β-galactosidase activity in fibrotic lungs and releases a stimulator of interferon genes (STING)-degrading PROTACs to suppress senescence-associated inflammatory signaling linked to impaired alveolar epithelial repair. FAP@BD is activated by fibroblast activation protein-α enriched in activated fibroblast-dominated fibrotic regions, delivering a bromodomain-containing protein 4 (BRD4)-degrading PROTAC to inhibit myofibroblast activation and extracellular matrix production. After inhalation, both nanoparticles exhibit efficient mucus penetration, improved pulmonary retention, and preferential accumulation in fibrotic lesions, enabling localized degradation of STING and BRD4. In a bleomycin-induced mouse model of pulmonary fibrosis, the combined PROTAC nanococktail achieves superior therapeutic efficacy compared with either single PROTAC nanoparticle, as demonstrated by restored lung architecture, improved respiratory function, reduced collagen deposition, and reversal of fibrosis-associated transcriptional programs. These results demonstrate an inhaled dual-PROTAC nanotherapeutic strategy for simultaneously attenuating epithelial senescence-associated inflammation and fibroblast-driven matrix remodeling.
Tan et al. (Wed,) studied this question.