Improving the Efficiency of Ultrasound and Microbubble Mediated Gene Delivery by Manipulation of Microbubble Lipid Composition

Ultrasound and microbubble-mediated gene delivery is emerging as a powerful nonviral gene delivery approach due to its ability to target various tissues. Since microbubble cavitation plays a crucial role in gene delivery, factors affecting cavitation, such as microbubble composition, size, ultrasound pressure, frequency, and pulse interval, can directly affect the efficiency of gene delivery. The effect of ultrasound parameters on gene delivery efficiency has been systematically investigated in numerous studies. However, relatively few studies have investigated the influence of different microbubble compositions on gene delivery. In this paper, we report that microbubbles made with the same lipids but different poly(ethylene glycol) (PEG) derivatives lead to significantly different gene delivery efficiencies <i>in vitro</i>. Moreover, we show that the type of PEG derivative used in microbubble formulations greatly influences the acoustic response of microbubbles (i.e., resonance frequency and frequency-dependent attenuation coefficient), thus explaining the differences in gene delivery efficiencies. Our results highlight that changing a single component in the microbubble formulation, i.e., the type of PEG derivative, can improve gene delivery efficiency by 3-fold. This comparative study of microbubbles made with different PEG derivatives may help researchers in designing microbubble formulations for optimal gene delivery.