Spatial-temporal-controlled NO gas and PARP1 siRNA delivery for alleviating the dilemma of deeper sonodynamic therapy in pancreatic cancer

Sonodynamic therapy for pancreatic cancer is always limited to poor drug delivery and resistance. The insufficient drug delivery is mostly associated with the abundant fibrotic stroma which consisting of a natural physical barrier. In addition, the activated DNA repair pathway associated with reactive oxygen (ROS) therapy greatly resist and weaken the SDT efficacy. Based on these facts, we herein presented an ultrasound responsive microbubble system of PARP1 siRNA-Pyropheophorbide/SNO (P-PPaS MBs), which were self-assembled by lipids covalently conjugated with Pyropheophorbide, DSPE-PEG2000-SNO, and DC-Chol, while the PARP1 siRNA was absorbed onto the surface of microbubbles. Upon local ultrasound irradiation, the in situ micro-nano conversion induced cavitation effect and spatial–temporal controlled release of NO mediated by ROS generated from pyropheophorbide could facilitate the deeper penetration of sonosensitizer and siRNA at pancreatic tumor sites. SDT could effectively kill tumor cells, while PARP1 inhibition blocked the DNA repair pathway to further enhance the tumor killing efficiency. Therefore, controlled NO self-supply and gene therapy assisted SDT had the potential to be an effective strategy for deeper pancreatic cancer therapy.