Biomimetic nanoparticles facilitating the functional engraftment of lung epithelial stem cells for silicosis therapy

Silicosis is an irreversible, progressive occupational lung disease caused by chronic inhalation of crystalline silica (SiO₂), with no approved disease-modifying therapies currently available. Its pathological hallmark is a hostile fibrotic microenvironment driven by excessive reactive oxygen species (ROS), chronic inflammation, and mitochondrial dysfunction in alveolar epithelial type 2 (AEC2) cells; this microenvironment is the primary bottleneck for stem cell-based silicosis therapy, as it severely impairs the engraftment of exogenous AEC2 cells. Metformin (Met) exerts mitochondria-protective effects to preserve AEC2 function, but its clinical translation for silicosis is limited by low oral bioavailability and non-specific systemic distribution. Here, we developed a ROS-responsive biomimetic liposome (TK-PSBs@Met, also termed TPM NPs) for targeted Met delivery to AEC2s in fibrotic lungs, via a design combining pulmonary surfactant (PS)-mediated AEC2 targeting and thioketal (TK)-based ROS-triggered on-demand drug release. In vitro, TPM NPs reversed SiO₂-induced epithelial-mesenchymal transition (EMT), suppressed fibrotic and inflammatory responses, and restored mitochondrial function in A549 cells, a well-established AEC2 cell model. In vivo, TPM NPs significantly boosted the functional engraftment of TdTomato⁺ AEC2 stem cells, promoted alveolar regeneration, and attenuated collagen deposition and inflammation in SiO₂-induced silicosis mice. Mechanistically, TPM NPs mitigated silicotic fibrosis via a dual synergistic mechanism: remodeling the hostile fibrotic microenvironment and activating the AMPK/PGC-1α/NRF1/TFAM signaling axis to restore AEC2 mitochondrial biogenesis. Collectively, this TPM NP-AEC2 combinatorial therapy offers a translatable precision strategy for silicosis treatment and establishes a new paradigm for nanomedicine-augmented stem cell therapy in refractory fibrotic lung diseases.