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Targeting Senescent Alveolar Type 2 Cells with a Gene-Editable FePt Dual-Atom Catalyst for Mitigating Idiopathic
Qianglan Lu1, Chengwei Ye1, Wei Mao1
1Department of Gastric and Hernia Surgery, Nanjing Drum Tower Hospital, College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing 210023, China.
Abstract:
Idiopathic pulmonary fibrosis (IPF) remains an age-related, fatal, incurable, epithelial-driven fibrotic lung disease despite the availability of approved antifibrotic drugs. The medical need for effective antipulmonary fibrotic therapies is thus very high. A promising therapeutic intervention for IPF is to target key cellular senescence processes in alveolar type 2 (AT2) cells. Herein, we introduce an inhalable gene-editable nanoplatform, comprising a CRISPR-Cas9 gene-editing system linked to a core FePt diatomic catalyst, encapsulated within a biocompatible hyaluronic acid (HA) surface layer (FePtR@HA). The FePt diatomic site facilitates H2O2 bridge adsorption, enabling efficient O-O bond cleavage and rapid catalytic conversion. The strong Fe-Pt interaction modulates the metal's d-band center, optimizing the adsorption of oxygen-containing intermediates. This precise regulation efficiently clears ROS, delivering robust antioxidant and antisenescence effects to AT2 cells. Simultaneously, the CRISPR-Cas9 gene editing system knocks down the pro-aging gene KAT7, reducing senescence-associated secretory phenotype (SASP) factors and further reversing AT2 cell senescence. Additionally, we demonstrated the antifibrotic efficacy of FePtR@HA in a lung-on-a-chip model, where it reprogrammed the fibrotic microenvironment, prevented myofibroblast recruitment to AT2 cells. Moreover, FePtR@HA showed satisfactory results in IPF mouse models, alleviating fibrosis and presenting a highly promising approach to combat the progression of IPF.
Insights
A novel inhalable nanoplatform, FePtR@HA, targets cellular senescence in alveolar type 2 cells to combat idiopathic pulmonary fibrosis (IPF). This approach combines gene editing and catalysis to reduce fibrosis and reverse lung disease progression.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Pulmonary Medicine
Background:
- Idiopathic pulmonary fibrosis (IPF) is a fatal, incurable lung disease with a high unmet medical need.
- Cellular senescence in alveolar type 2 (AT2) cells is a key driver of IPF.
- Current antifibrotic therapies have limitations, necessitating novel therapeutic strategies.
Purpose of the Study:
- To develop and evaluate an inhalable gene-editable nanoplatform for treating IPF.
- To target cellular senescence and reduce fibrosis in AT2 cells.
- To investigate the therapeutic potential of the nanoplatform in preclinical models.
Main Methods:
- Development of an inhalable nanoplatform (FePtR@HA) combining CRISPR-Cas9 gene editing and a FePt diatomic catalyst with a hyaluronic acid coating.
- Utilizing the FePt catalyst to clear reactive oxygen species (ROS) and reduce oxidative stress in AT2 cells.
- Employing CRISPR-Cas9 to knock down the pro-aging gene KAT7, thereby reducing senescence-associated secretory phenotype (SASP) factors.
- Evaluating the nanoplatform's efficacy in a lung-on-a-chip model and IPF mouse models.
Main Results:
- The FePtR@HA nanoplatform demonstrated efficient ROS clearance and antioxidant effects in AT2 cells.
- Gene editing of KAT7 successfully reduced SASP factors and reversed AT2 cell senescence.
- The nanoplatform reprogrammed the fibrotic microenvironment in a lung-on-a-chip model, inhibiting myofibroblast recruitment.
- FePtR@HA significantly alleviated lung fibrosis in IPF mouse models.
Conclusions:
- The inhalable FePtR@HA nanoplatform offers a dual-action therapeutic strategy for IPF by addressing cellular senescence and fibrosis.
- This approach shows significant promise for combating the progression of idiopathic pulmonary fibrosis.
- FePtR@HA represents a highly promising therapeutic intervention for age-related fibrotic lung diseases.
