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

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 (FPN AI ) were developed. FPN AI 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 AI triggered immunogenic cell death, characterized by dendritic cell maturation and activation of cytotoxic CD8⁺ T cells. In vivo studies demonstrated that FPN AI 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 FPN AI 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.