Deteng Zhang,1– 4 Jinxiao Song,4 Zhenghui Jing,4 Huan Qin,4 You Wu,3 Jingyi Zhou,4 Xinlong Zang1– 4 

1The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, People’s Republic of China; 2Qingdao Cancer Institute, Qingdao University, Qingdao, People’s Republic of China; 3Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Qingdao, People’s Republic of China; 4School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, People’s Republic of China

Correspondence: Xinlong Zang, Email zangxinlong@126.com

Background: Hepatocellular carcinoma (HCC) is a serious global health concern, accounting for about 90% of all liver cancer instances. Surgical treatment is a fundamental aspect of HCC management; however, the challenge of postoperative recurrence significantly impacts mortality rates.
Methods: We have developed a pH and reactive oxygen species (ROS) dual stimulus-responsive drug delivery system (PN@GPB-PEG NPs) loaded with chemotherapeutic paclitaxel (PTX) and indoleamine 2.3-dioxygenase (IDO) inhibitor NLG919, for HCC chemoimmunotherapy. The physiochemical properties, such as particle size, zeta potential, morphology, and encapsulation efficiency, were characterized. Furthermore, we investigated in vitro cytotoxicity, cellular uptake and immunogenic cell death in tumor cells treated with our nanoparticles. In vivo biodistribution, antitumor effects and immune responses were assessed in an HCC mice model.
Results: PN@GPB-PEG NPs display pH-responsive properties with improved targeting abilities toward tumors and improved uptake by HCC cells. Upon exposure to oxygen peroxide (H2O2), the sophisticated design allows for rapid release of therapeutic agents. In this process, PTX induces immunogenic cell death (ICD), which activates the immune system to generate an antitumor response. Simultaneously, NLG919 works to inhibit IDO, mitigating the immunosuppressive environment. This combination strategy leverages the advantages of both chemotherapy and immunotherapy, resulting in a powerful synergistic antitumor effect. In a mouse model of HCC, our nanoparticles effectively inhibited the growth of primary and recurrent tumors.
Conclusion: These encouraging results highlight the potential of our nanocarrier system as an innovative therapeutic approach to address HCC primary tumor and postsurgical recurrence, providing hope for enhanced patient outcomes.

Keywords: hepatocellular carcinoma (HCC), nanoparticles, stimuli responsiveness, chemoimmunotherapy, paclitaxel (PTX), NLG919