Efficient Delivery of Genetic Constructs to Uterine Fibroid Cells Using Peptide Nanocomplexes

Uterine fibroids are a prevalent clinical concern in gynecology, and current surgical interventions, myomectomy and hysterectomy, pose risks of complications and potentially compromise reproductive function. Given the limitations of conventional treatments, there is a significant need for organ-sparing alternatives, such as gene therapy.
This study addresses the development of non-viral gene delivery strategies for uterine fibroids. Traditional viral vectors present substantial risks, including immunogenicity, insertional mutagenesis, and limitations in repeated administration. Non-viral systems for uterine fibroid therapy remain relatively unexplored despite their potential for localized treatment and reduced systemic effects.
We developed a novel ternary peptide-based system incorporating both cationic and anionic peptide components to address limitations of conventional binary complexes. The inclusion of anionic peptides enhances complex stability via improved charge distribution, promotes efficient cellular internalization, and reduces nonspecific interactions with biological constituents. Our optimization strategy focused on two key parameters: minimizing complex formation volume while maintaining therapeutic DNA payload, and determining optimal charge ratios between DNA, cationic and anionic peptides.
Comprehensive physicochemical characterization included analysis of hydrodynamic properties via dynamic light scattering (DLS), surface charge assessment via zeta potential measurements, DNA binding capacity evaluation, and investigation of release kinetics. Biological evaluation demonstrated preserved cellular viability and significantly enhanced transfection efficiency in both cell culture models and ex vivo fibroid tissue. The system achieved consistent particle sizes below 200 nm with favorable surface charge characteristics for cellular uptake.
These findings suggest that this optimized ternary peptide system represents a robust and efficient platform for gene delivery to uterine fibroid cells, offering a promising organ-preserving approach for translational gene therapy applications.