aPD-L1-facilitated theranostic and tumor microenvironment remodeling of pancreatic cancer via docetaxel-loaded phase-transformation nanoparticles triggered by low-intensity pulsed ultrasound

Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenging because of its depth, which often leads to misdiagnosis during ultrasound examinations. The unique PDAC tumor microenvironment (TME) is characterized by significant fibrous tissue growth, and high interstitial pressure hinders drug penetration into tumors. Additionally, hypoxia and immune suppression within the tumor contribute to poor responses to radiotherapy and chemotherapy, ultimately leading to an unfavorable prognosis. In this study, aPD-L1-modified docetaxel and perfluoropentane-loaded liquid‒vapor phase-transformation lipid nanoparticles (aPDL1-DTX/PFP@Lipid) were synthesized and had an average diameter of 61.63 nm with 84.3% antibody modification. We demonstrated that the nanoparticles (NPs) exhibited excellent PDAC-targeting capabilities both in vitro and in vivo. Upon exposure to low-intensity pulsed ultrasound (LIPUS) stimulation, the NPs underwent a phase transformation to form microbubbles with substantial molecular ultrasound diagnostic effects, and combined treatment resulted in a tumor growth inhibition rate of 88.91%. This treatment strategy also led to the infiltration of CD8⁺ T cells, the downregulation of Treg cells, the promotion of M1 macrophage polarization, the inhibition of fibrosis to reduce tumor stromal pressure, and the facilitation of perfluoropentane (PFP) gasification to release O₂ and improve tumor hypoxia. In conclusion, aPD-L1-modified liquid‒vapor phase-transformation nanoparticles loaded with docetaxel (DTX) and PFP were successfully combined with ultrasound for the molecular diagnosis and targeted treatment of PDAC. aPDL1-DTX/PFP@Lipid could reshape the PDAC TME, offering a new approach for ultrasound-mediated diagnosis and treatment with promising clinical applications.

Contrast-enhanced ultrasound; Molecular diagnosis; Pancreatic cancer; Targeted therapy; Tumor microenvironment.