Sono-Immunotherapy Mediated Controllable Composite Nano Fluorescent Probes Reprogram the Immune Microenvironment of Hepatocellular Carcinoma

Yichi Chen,1– 3 Bolin Wu,1– 3 Haitao Shang,1– 3 Yucao Sun,1– 3 Huimin Tian,1– 3 Huajing Yang,1– 3 Chunyue Wang,1– 3 Xiaodong Wang,1– 3 Wen Cheng1– 3 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 2Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 3Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin, 150081, People’s Republic of ChinaCorrespondence: Wen Cheng, Department of Ultrasound, Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86 13313677182, Fax +86 451 85718392, Email chengwen@hrbmu.edu.cnBackground: Despite the clinical efficacy of immunotherapy in treating malignant tumors, its effectiveness is often hampered by the immunosuppressive nature of the tumor microenvironment (TME). In this study, we propose the design of a nanoscale ultrasound contrast agent capable of triggering macrophage polarization and immunogenic cell death (ICD) for the treatment of hepatocellular carcinoma (HCC) through sonodynamic treatment (SDT) and immunotherapy.Methods: The re-educator (designated as ICG@C3F8-R848 NBs) is composed of the Toll-like receptor agonist resiquimod (R848) and the sonosensitizer Indocyanine green (ICG), utilizing nanobubbles (NBs) as carriers. The technique known as ultrasound-targeted nanobubble destruction (UTND) employs nanosized microbubbles and low-frequency ultrasound (LFUS) to ensure accurate drug delivery and enhance safety.Results: Following intravenous delivery, ICG@C3F8-R848 NBs have the potential to selectively target and treat primary tumors using SDT in conjunction with ultrasonography. Importantly, R848 can enhance antitumor immunity by inducing the polarization of macrophages from an M2 to an M1 phenotype.Conclusion: The SDT-initiated immunotherapy utilizing ICG@C3F8-R848 NBs demonstrates significant tumor suppression effects with minimal risk of systemic toxicity. The utilization of this self-delivery re-education technique would contribute to advancing the development of nanomedicine for the treatment of hepatocellular carcinoma.Keywords: hepatocellular carcinoma, synergistic sono-immunotherapy strategy, tumor-associated-macrophage