We have previously applied ultrasound (US) with microbubbles (MBs) to enhance inner ear drug delivery, with most experiments conducted using single‐frequency, high‐power density US, and multiple treatments. In the present study, the treatment efficacy was enhanced and safety concerns were addressed using a combination of low‐power‐density, single‐transducer, dual‐frequency US (ISPTA = 213 mW/cm2) and MBs of different sizes coated with insulin‐like growth factor 1 (IGF‐1). This study is the first to investigate the drug‐coating capacity of human serum albumin (HSA) MBs of different particle sizes and their drug delivery efficiency. The concentration of HSA was adjusted to produce different MB sizes. The drug‐coating efficiency was significantly higher for large‐sized MBs than for smaller MBs. In vitro Franz diffusion experiments showed that the combination of dual‐frequency US and large MB size delivered the most IGF‐1 (24.3 ± 0.47 ng/cm2) to the receptor side at the second hour of treatment. In an in vivo guinea pig experiment, the efficiency of IGF‐1 delivery into the inner ear was 15.9 times greater in animals treated with the combination of dual‐frequency US and large MBs (D‐USMB) than in control animals treated with round window soaking (RWS). The IGF‐1 delivery efficiency was 10.15 times greater with the combination of single‐frequency US and large size MBs (S‐USMB) than with RWS. Confocal microscopy of the cochlea showed a stronger distribution of IGF‐1 in the basal turn in the D‐USMB and S‐USMB groups than in the RWS group. In the second and third turns, the D‐USMB group showed the greatest IGF‐1 distribution. Hearing assessments revealed no significant differences among the D‐USMB, S‐USMB, and RWS groups. In conclusion, the combination of single‐transducer dual‐frequency US and suitably sized MBs can significantly reduce US power density while enhancing the delivery of large molecular weight drugs, such as IGF‐1, to the inner ear.

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