Antisense oligonucleotides hold therapeutic promise for various lung disorders, but their efficacy is limited by suboptimal delivery. To address this challenge, we explored the use of inhaled bottlebrush polymer-DNA conjugates, named pacDNA, as a delivery strategy. Inhaled pacDNA exhibits superior mucus penetration, achieving a uniform and sustained lung distribution in mice. Targeting the 5' splice site of an aberrant enhanced green fluorescence protein ( EGFP ) pre-mRNA in EGFP-654 mice, inhaled pacDNA more efficiently corrects splicing than a B-peptide conjugate and restores EGFP expression in the lung. Additionally, in an orthotopic NCI-H358 non-small-cell lung tumor mouse model, inhaled pacDNA targeting wild-type KRAS mRNA effectively suppresses KRAS expression and inhibits lung tumor growth, requiring a substantially lower dosage compared to intravenously injected pacDNA. These findings demonstrate the potential of bottlebrush polymer-DNA conjugates as a promising agent for enhanced oligonucleotide therapy in the lung and advancing the treatment landscape for lung disorders.
Keyphrases
- wild type
- cystic fibrosis
- mouse model
- cancer therapy
- poor prognosis
- binding protein
- single molecule
- stem cells
- pulmonary hypertension
- nucleic acid
- single cell
- adipose tissue
- cell therapy
- machine learning
- type diabetes
- high fat diet induced
- bone marrow
- circulating tumor
- climate change
- insulin resistance
- metabolic syndrome
- small molecule
- mesenchymal stem cells
- combination therapy