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Improving Nonviral Gene Delivery by Activating Mechanosensing-Dependent Endocytic Pathways.
Flaminia Fruzzetti1, Beatrice Ruzzante1, Eleonora Giagnorio2
1genT_LΛB, Dept. of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Via Bassini 6, Milan 20133, Italy.
ACS Applied Materials & Interfaces
|January 8, 2026
Summary
Mechanical stimulation enhances gene delivery by improving cellular uptake and nuclear access. This mechanobiological approach boosts the efficiency of non-viral gene delivery vectors without altering their chemistry.
Area of Science:
- Biotechnology
- Cell Biology
- Biomedical Engineering
Background:
- Nucleic acid delivery is crucial for treating diseases, but cellular barriers hinder current nanoparticle technologies.
- Non-viral gene delivery systems face challenges with transfection efficiency (TE).
Purpose of the Study:
- To investigate if mechanical stimulation can enhance the TE of non-viral gene delivery vectors.
- To explore the cellular mechanisms underlying mechanically induced improvements in gene delivery.
Main Methods:
- Developed a device for uniaxial cyclic stretching of cells.
- Applied mechanical stimulation (0.1 Hz, 10% strain, 30 min) to HeLa cells and human myoblasts (hMyo).
- Analyzed changes in nuclear translocation of YAP and gene expression related to endocytosis.
Main Results:
- Cyclic mechanical stimulation significantly increased nuclear translocation of YAP.
- Mechanical conditioning modulated endocytic pathways, upregulating clathrin-mediated endocytosis and macropinocytosis.
- Enhanced TE of plasmid DNA and mRNA using branched polyethylenimine (bPEI) vectors in both cell types.
Conclusions:
- Mechanical stimulation is a viable strategy to improve non-viral gene delivery by utilizing cellular mechanotransduction.
- This approach enhances existing delivery systems by optimizing cellular uptake and nuclear accessibility.
- Mechanobiological methods offer new avenues for ex vivo cell engineering and gene therapy.
