Lipid nanocomposites for precisely triggered Ttc3 gene silencing in pulmonary fibrosis treatment
Letong Li1, Yaxuan Liang2, Peipei Yin1
1Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disorder with limited therapeutic options. The tetratricopeptide repeat domain 3 (TTC3) gene, located on chromosome 21, has poorly defined biological functions. By generating Ttc3 knockout mice, we found that lacking Ttc3 led to severe pulmonary development defects after birth, indicating its essential role in lung homeostasis. In this study, we identified Ttc3 as a critical regulator in the progression of pulmonary fibrosis by activating the PI3K/Akt signaling pathway, suggesting that Ttc3 might be a potential target for IPF treatment. Here, we developed a lipid-polymer hybrid nanocarrier (TMD) engineered to encapsulate and control release of small interfering RNA (siRNA), and demonstrated that the TMD exhibited optimal particle size and improved structural stability, high biocompatibility, and efficient transfection efficiency in lung tissue. In the bleomycin (BLM)-induced pulmonary fibrosis mouse model, siTtc3@TMD effectively knocked down Ttc3 expression in lung tissue, significantly inhibited the activation of PI3K/Akt signaling pathway, mitigated lung tissue pathological damage, preserved pulmonary function, and ultimately alleviated pulmonary fibrosis. In summary, our study highlights both a novel therapeutic target (Ttc3) and a safe, efficient siRNA delivery platform, providing a promising strategy for the treatment of pulmonary fibrosis.
Insights
Tetratricopeptide repeat domain 3 (TTC3) is crucial for lung homeostasis and a new target for idiopathic pulmonary fibrosis (IPF). A novel nanocarrier effectively delivered siRNA to reduce TTC3, significantly improving lung function in a mouse model.
Area of Science:
- Pulmonary Medicine
- Genetics
- Nanotechnology
Background:
- Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with few treatments.
- The role of the tetratricopeptide repeat domain 3 (TTC3) gene in lung function is largely unknown.
- TTC3's involvement in activating the PI3K/Akt pathway suggests a potential role in fibrosis.
Purpose of the Study:
- To investigate the role of TTC3 in pulmonary fibrosis.
- To develop and evaluate a novel siRNA delivery system for targeting TTC3 in lung tissue.
- To assess the therapeutic potential of TTC3 inhibition for IPF treatment.
Main Methods:
- Generated Ttc3 knockout mice to study lung development and homeostasis.
- Developed a lipid-polymer hybrid nanocarrier (TMD) for siRNA encapsulation and controlled release.
- Utilized a bleomycin (BLM)-induced pulmonary fibrosis mouse model to test siTtc3@TMD efficacy.
Main Results:
- TTC3 deficiency caused severe pulmonary development defects, highlighting its importance in lung homeostasis.
- The developed TMD system demonstrated optimal particle size, stability, biocompatibility, and transfection efficiency.
- siTtc3@TMD treatment in the BLM model significantly reduced Ttc3 expression, inhibited the PI3K/Akt pathway, and alleviated lung damage and fibrosis.
Conclusions:
- TTC3 is identified as a critical regulator in pulmonary fibrosis progression via the PI3K/Akt pathway.
- The lipid-polymer hybrid nanocarrier (TMD) serves as an effective and safe platform for siRNA delivery to lung tissue.
- Targeting TTC3 with siRNA delivered via TMD presents a promising therapeutic strategy for treating pulmonary fibrosis.
