Because of the absence of tolerable and effective carriers for in vivo delivery, the applications of
small interfering RNA (
siRNA) in the clinic for therapeutic purposes have been limited. In this study, development of a novel
siRNA delivery system based on ultrasound-sensitive nanobubbles (NBs, nano-sized echogenic
liposomes) and cell-permeable
peptides (CPPs) is described. A
CPP-
siRNA conjugate was entrapped in an NB, (
CPP-
siRNA)-NB, and the penetration of
CPP-
siRNA was temporally masked; local ultrasound stimulation triggered the release of
CPP-
siRNA from the NBs and activated its penetration. Subsequent research revealed that the (
CPP-
siRNA)-NBs had a mean particle size of 201 ± 2.05 nm and a
siRNA entrapment efficiency >85%. In vitro release results indicated that >90% of the encapsulated
CPP-
siRNA was released from NBs in the presence of ultrasound, whereas <1.5% (30 min) was released in the absence of ultrasound. Cell experiments indicated higher cellular
CPP-
siRNA uptake of (
CPP-
siRNA)-NBs with ultrasound among the various formulations in human breast
adenocarcinoma cells (HT-1080). Additionally, after systemic administration in mice, (
CPP-
siRNA)-NBs accumulated in the
tumor, augmented c-myc silencing and delayed
tumor progression. In conclusion, the application of (
CPP-
siRNA)-NBs with ultrasound may constitute an approach to selective targeted delivery of
siRNA.