Ultrasound-responsive curcumin/miR-16-5p co-loaded nanobubbles enhance antitumor immunity in hepatocellular carcinoma via ICD induction and PD-L1 suppression.

Despite the notable clinical advances brought about by programmed cell death ligand 1/programmed death 1 (PD-1/PD-L1) inhibitors in hepatocellular carcinoma (HCC) therapy, the tumor immunosuppressive microenvironment (TIME) exerts a restrictive effect on their overall therapeutic performance. To overcome the constraints imposed by TIME, this study developed an innovative targeted therapeutic strategy leveraging ultrasound-responsive nanobubbles (NBs) for the co-delivery of curcumin and miR-16-5p (Cur/miR-16-NBs)，a dual-functional platform rationally constructed to achieve synergism between PD-L1 suppression and immunogenic cell death (ICD) induction. The NBs were rationally engineered to exhibit spherical morphology. Only average particle size was quantified in this work, while polydispersity index and zeta potential data were not recorded, with quantitative characterization confirming high encapsulation efficiency of both miR-16-5p and curcumin. MiR-16-5p can downregulate the expression of PD-L1, inhibit the PD-1/PD-L1 signaling pathway. Meanwhile, as a safe and effective sonosensitizer, curcumin can generate abundant ROS under ultrasound irradiation to trigger ICD further promoting tumor cells to release three key signals-calreticulin (CRT), adenosine triphosphate (ATP), and high-mobility group box 1 protein (HMGB1), activate dendritic cells and boost CTL-mediated anti-tumor activity, thereby partially alleviating local tumor immunosuppression. Combined miR-16-5p and curcumin can activate intratumoral T lymphocytes to a certain degree and exert synergistic tumor-killing effects.Collectively, these findings highlight the potential of Cur/miR-16-NBs as an effective therapeutic platform for HCC, offering a precision medicine approach to improve treatment efficacy.