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Background <p>Navitoclax (ABT-263) exhibits strong cytotoxic effects against hepatocellular carcinoma cells in vitro; however, its therapeutic efficacy in vivo is limited by insufficient local drug accumulation and compensatory upregulation of the anti-apoptotic protein myeloid cell leukemia-1 during long-term treatment. In addition, effective immune activation in hepatocellular carcinoma remains challenging due to the immune-privileged hepatic microenvironment. This study aimed to overcome these limitations through a tumor-targeted nanotherapeutic strategy.</p> Results <p>Dual pH-responsive copolymeric nanoparticles modified with folic acid and co-loaded with navitoclax and indocyanine green (FPN<sub>AI</sub>) were developed. FPN<sub>AI</sub> preferentially accumulated at hepatocellular carcinoma sites through folate receptor–mediated targeting and released navitoclax in response to the acidic tumor microenvironment, thereby inducing mitochondria-mediated apoptosis. Upon near-infrared irradiation, indocyanine green generated excessive reactive oxygen species, leading to downregulation of myeloid cell leukemia-1 and further enhancement of apoptotic signaling. The combined effects of navitoclax and reactive oxygen species synergistically promoted tumor cell apoptosis. Moreover, apoptosis induced by FPN<sub>AI</sub> triggered immunogenic cell death, characterized by dendritic cell maturation and activation of cytotoxic CD8⁺ T cells. In vivo studies demonstrated that FPN<sub>AI</sub> with near-infrared irradiation achieved significantly improved antitumor efficacy compared with navitoclax monotherapy, while maintaining favorable tumor-targeting capability and biosafety.</p> Conclusions <p>This study demonstrates that FPN<sub>AI</sub> enhances the antitumor activity of navitoclax by integrating targeted drug delivery, reactive oxygen species–mediated mitochondrial apoptosis, and immunogenic cell death induction. The proposed nanotherapeutic platform represents a promising approach for improving hepatocellular carcinoma treatment outcomes.</p> Graphical Abstract <p></p>

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Navitoclax-encapsulated dual pH-responsive copolymeric nanoparticles improves hepatocellular carcinoma treatment with induction of apoptosis and immune activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Jiahao Wang,
  • Tianao Xie,
  • Heng Jiang,
  • Yukai Shan,
  • Sarun Juengpanich,
  • Shijie Li,
  • Win Topatana,
  • Yeling Liu,
  • Hong Wan,
  • Yeben Qian,
  • Peng Chen,
  • Bo Chen

摘要

Background

Navitoclax (ABT-263) exhibits strong cytotoxic effects against hepatocellular carcinoma cells in vitro; however, its therapeutic efficacy in vivo is limited by insufficient local drug accumulation and compensatory upregulation of the anti-apoptotic protein myeloid cell leukemia-1 during long-term treatment. In addition, effective immune activation in hepatocellular carcinoma remains challenging due to the immune-privileged hepatic microenvironment. This study aimed to overcome these limitations through a tumor-targeted nanotherapeutic strategy.

Results

Dual pH-responsive copolymeric nanoparticles modified with folic acid and co-loaded with navitoclax and indocyanine green (FPNAI) were developed. FPNAI preferentially accumulated at hepatocellular carcinoma sites through folate receptor–mediated targeting and released navitoclax in response to the acidic tumor microenvironment, thereby inducing mitochondria-mediated apoptosis. Upon near-infrared irradiation, indocyanine green generated excessive reactive oxygen species, leading to downregulation of myeloid cell leukemia-1 and further enhancement of apoptotic signaling. The combined effects of navitoclax and reactive oxygen species synergistically promoted tumor cell apoptosis. Moreover, apoptosis induced by FPNAI triggered immunogenic cell death, characterized by dendritic cell maturation and activation of cytotoxic CD8⁺ T cells. In vivo studies demonstrated that FPNAI with near-infrared irradiation achieved significantly improved antitumor efficacy compared with navitoclax monotherapy, while maintaining favorable tumor-targeting capability and biosafety.

Conclusions

This study demonstrates that FPNAI enhances the antitumor activity of navitoclax by integrating targeted drug delivery, reactive oxygen species–mediated mitochondrial apoptosis, and immunogenic cell death induction. The proposed nanotherapeutic platform represents a promising approach for improving hepatocellular carcinoma treatment outcomes.

Graphical Abstract