**Abstract**

Gene therapy has been widely explored as a pharmacological approach, with a great potential to treat various diseases. Generally, many diseases have definite lesion's site, especially for tumors. This feature results in a great demand on the delivery of therapeutic gene to the local lesion's site. Ultrasound combined with microbubbles provides a promising platform to deliver gene in a spatiotemporally controlled way. Ultrasound beam can be positioned and targeted onto the deepseated lesion's site of diseases by an external mobile transducer. Microbubbles can serve as vehicles for carrying genetic cargo and can be destructed by ultrasound, resulting in the local release of genetic payload. Meanwhile, sonoporation effect will occur upon which the bubbles are exposed to the appropriate ultrasonic energy, producing the transient small holes on the adjacent cell membrane and thus increasing the vascular and cellular permeability. In this chapter, we will review the recent advances about local gene delivery by ultrasound.

**Keywords:** ultrasound, gene therapy, microbubbles, sonoporation

## **1. Introduction**

Gene therapy, designed to deliver nucleic acid into cells to compensate for abnormal genes, is now considered a promising treatment option for some human diseases [1]. With the development of modern medicine and precise medicine, there is an increasing trend to change the traditional gene delivery mode into local gene delivery. At present, there are mainly two gene delivery approaches, virusmediated transfection and nonvirus-mediated transfection [2]. The former method has high-transfection efficiency, but the preparation procedure of recombinant viruses is sophisticated, and their clinical application is restricted due to biosafety concerns [3]. Nonviral vector approaches, such as liposome-mediated methods and electroporation techniques, are relatively safe. However, poor targeting and low-transfection efficiencies limit their widespread use [4]. It is a current research hotspot to look for an effective and safe method to mediate gene delivery for biomedical application.

Ultrasound is a widely used diagnostic technique in clinic, which possesses the advantages of safety, real-time monitoring, and low cost. Recently, with the development of ultrasound contrast agents, ultrasound has evolved from a diagnostic tool to a treatment application for delivering locally therapeutic substances into the lesion's sites. Ultrasound-targeted microbubble destruction (UTMD) provides a promising platform to deliver genes in a spatiotemporally controlled way.

#### **Figure 1.**

*Schematic model of ultrasound-mediated gene delivery. Bioeffect produced by ultrasound and microbubble interaction could enhance the permeability of vascular and promote the accumulation of gene (green) in tissue. (Quoted from: Sirsi and Borden [5]).*

Microbubbles can serve as vehicles for carrying genetic cargo and can be destructed by ultrasound, resulting in the local release of genetic payload. Meanwhile, sonoporation effect will occur upon which the bubbles are exposed to the appropriate ultrasonic energy, producing the transient small holes on the adjacent cell membrane and thus increasing the vascular and cellular permeability **Figure 1**. In this chapter, we will briefly introduce the mechanism and review the recent advances about local gene delivery by ultrasound.
