Isorhamnetin and anti-PD-L1 antibody dual-functional mesoporous silica nanoparticles improve tumor immune microenvironment and inhibit YY1-mediated tumor progression

• Published in: Journal of nanobiotechnology 2023-07, Vol.21 (1), p.208-208, Article 208
• Main Authors: Liu, Huijuan, Han, Jingxia, Lv, Ying, Zhao, Zihan, Zheng, Shaoting, Sun, Yu, Sun, Tao
• Format: Article
• Language: English
• Subjects: Anti-PD-L1 monoclonal antibody; Antibodies; Bioflavonoids; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Care and treatment; Cell Line, Tumor; Cell proliferation; Chemical properties; Controlled release; Degradation; Development and progression; Dosage and administration; Drug delivery systems; Drug development; Drug therapy; Drugs; Epithelial–mesenchymal transformation (EMT); Flavones; Flavonoids; Health aspects; Hepatocellular carcinoma; Hepatoma; Hereditary Sensory and Motor Neuropathy; Humans; Immune checkpoint inhibitors; Immunoprecipitation; Immunotherapy; Isorhamnetin; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Lymphocytes T; Manufacturers; Medical prognosis; Membranes; Mesoporous silica nanoparticles; Metastases; Metastasis; Monoclonal antibodies; Nanoparticles; PD-L1 protein; Plasmids; Proteins; Silica; Silicon dioxide; Transcription factors; Tumor cells; Tumor Microenvironment; Tumors; Ubiquitin; Ubiquitin-Specific Peptidase 7; Ubiquitin-specifific protease 7 (USP7); Ubiquitins - pharmacology; Yin-yang-1 (YY1); YY1 protein; YY1 Transcription Factor - metabolism
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-023-01967-3

The immune checkpoint inhibitor (ICI) anti-PD-L1 monoclonal antibody can inhibit the progress of hepatocellular carcinoma (HCC). Epithelial-mesenchymal transformation (EMT) can promote tumor migration and the formation of immune-suppression microenvironment, which affects the therapeutic effect of ICI. Yin-yang-1 (YY1) is an important transcription factor regulating proliferation, migration and EMT of tumor cells. This work proposed a drug-development strategy that combined the regulation of YY1-mediated tumor progression with ICIs for the treatment of HCC. We first studied the proteins that regulated YY1 expression by using pull-down, co-immunoprecipitation, and duo-link assay. The active compound regulating YY1 content was screened by virtual screening and cell-function assay. Isorhamnetin (ISO) and anti-PD-L1 antibody dual-functional mesoporous silica nanoparticles (HMSN-ISO@ProA-PD-L1 Ab) were prepared as an antitumor drug to play a synergistic anti-tumor role. YY1 can specifically bind with the deubiquitination enzyme USP7. USP7 can prevent YY1 from ubiquitin-dependent degradation and stabilize YY1 expression, which can promote the proliferation, migration and EMT of HCC cells. Isorhamnetin (ISO) were screened out, which can target USP7 and promote YY1 ubiquitin-dependent degradation. The cell experiments revealed that the HMSN-ISO@ProA-PD-L1 Ab nanoparticles can specifically target tumor cells and play a role in the controlled release of ISO. HMSN-ISO@ProA-PD-L1 Ab nanoparticles inhibited the growth of Hepa1-6 transplanted tumors and the effect was better than that of PD-L1 Ab treatment group and ISO treatment group. HMSN-ISO@ProA-PD-L1 Ab nanoparticles also exerted a promising effect on reducing MDSC content in the tumor microenvironment and promoting T-cell infiltration in tumors. The isorhamnetin and anti-PD-L1 antibody dual-functional nanoparticles can improve tumor immune microenvironment and inhibit YY1-mediated tumor progression. This study demonstrated the possibility of HCC treatment strategies based on inhibiting USP7-mediated YY1 deubiquitination combined with anti-PD-L1 monoclonal Ab.