Inhalable HUCMSC-Lipo biomimetic formulation inhibits fibroblast activation in mouse and non-human primate pulmonary fibrosis models.

Pulmonary fibrosis (PF) is a progressive and fatal lung disorder driven by abnormal fibroblast activation and excessive extracellular matrix (ECM) deposition, leading to structural and functional decline. Existing therapies can slow progression but fail to interrupt fibrotic remodeling. Here, we engineered HUCMSC-Lipo, an inhalable biomimetic formulation fusing human umbilical cord mesenchymal stem cell (HUCMSC) membranes with artificial phospholipids, with formulation parameters systematically optimized using a Bayesian optimization (BO) framework to ensure structural stability and nebulization compatibility. HUCMSC-Lipo maintained membrane functionality and structural integrity for effective nebulized delivery. We successfully established a non-human primate (NHP) PF model and innovatively developed a multidimensional evaluation framework. Utilizing a range of methods, including but not limited to positron emission tomography/computed tomography (PET/CT) molecular imaging with radiolabeled fibroblast activation protein (FAP) inhibitors, we confirmed that HUCMSC-Lipo suppressed fibrotic progression and restored pulmonary function by targeting the regulation of fibroblast activation. Mechanistically, THY-1 enrichment in HUCMSC-Lipo bound integrin receptors to block the FAK/PI3K signaling cascade and restore fibroblast mechanosensitivity, fundamentally turning off the pathological activation "switch" in fibroblasts. Our work presents an inhalable biomimetic formulation that combines therapeutic efficacy with synthetic accessibility, offering a mechanism-targeted approach to PF treatment with strong clinical translatability.