Enhancing curcumol delivery through PD-1 targeted nanocarriers: A novel therapeutic approach for prostate cancer.

BACKGROUND: Prostate cancer is a prevalent form of cancer that impacts men on a global scale, and its treatment faces challenges such as tumor metastasis, immune resistance, and epigenetic abnormalities. Most current research focuses on nanocarriers with a single function, but the dual mechanism of action-enhancing immune response and regulating EZH2 epigenetic modification-has not been reported.

PURPOSE: This study is the first to construct an engineered outer membrane vesicle (OMV) delivery system loaded with PD-1 antibody and Curcumol, combining two cutting-edge approaches: tumor immunotherapy and epigenetic regulation. We developed a nanocarrier system based on engineered OMVs (OMV-PD-1) to deliver the natural anticancer compound Curcumol, aiming to regulate epigenetic modifications and enhance tumor immune responses, thereby effectively inhibiting the proliferation and metastasis of prostate cancer cells.

METHODS: OMV-PD-1 was prepared using recombinant technology, and its characteristics were identified through the application of liquid chromatography-mass spectrometry (LC-MS), dynamic light scattering (DLS), and transmission electron microscopy (TEM). We assessed its antitumor activity against prostate cancer cells (PC3) in vitro and in vivo and explored its molecular mechanisms through RNA sequencing and gene set enrichment analysis (GSEA).

RESULTS: An outstanding encapsulation efficiency and a delayed drug release profile were evident in OMV-PD-1/Curcumol. In vitro experiments demonstrated that the system significantly inhibited PC3 cell migration (77.25 % inhibition) and invasion (73.03 % inhibition), and regulated histone methylation modifications (such as H3K9 and H3K27) by downregulating EZH2 gene expression. In vivo experiments confirmed its excellent tumor targeting in a humanized mouse model, significantly inhibiting tumor growth and enhancing immune responses, such as increased NK cell infiltration and elevated pro-inflammatory cytokine levels.

CONCLUSION: The OMV-PD-1/Curcumol delivery system developed in this study not only hinders the aggressive actions of prostate cancer cells by regulating epigenetic modifications but also significantly stimulates antitumor immune responses, offering a unique and readily implementable therapeutic avenue.