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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Dual pH-responsive copolymeric nanoparticles modified with folic acid and co-loaded with navitoclax and indocyanine green (FPN\n                      <jats:sub>AI<\/jats:sub>\n                      ) were developed. FPN\n                      <jats:sub>AI<\/jats:sub>\n                      preferentially accumulated at hepatocellular carcinoma sites through folate receptor\u2013mediated 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\n                      <jats:sub>AI<\/jats:sub>\n                      triggered immunogenic cell death, characterized by dendritic cell maturation and activation of cytotoxic CD8\u207a T cells. In vivo studies demonstrated that FPN\n                      <jats:sub>AI<\/jats:sub>\n                      with near-infrared irradiation achieved significantly improved antitumor efficacy compared with navitoclax monotherapy, while maintaining favorable tumor-targeting capability and biosafety.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study demonstrates that FPN\n                      <jats:sub>AI<\/jats:sub>\n                      enhances the antitumor activity of navitoclax by integrating targeted drug delivery, reactive oxygen species\u2013mediated mitochondrial apoptosis, and immunogenic cell death induction. The proposed nanotherapeutic platform represents a promising approach for improving hepatocellular carcinoma treatment outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12951-026-04733-3","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:44:57Z","timestamp":1784036697000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Navitoclax-encapsulated dual pH-responsive copolymeric nanoparticles improves hepatocellular carcinoma treatment with induction of apoptosis and immune activation"],"prefix":"10.1186","volume":"24","author":[{"given":"Jiahao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianao","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukai","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarun","family":"Juengpanich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Win","family":"Topatana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeben","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"4733_CR1","doi-asserted-by":"publisher","unstructured":"Rl S, Kd M, Ns W, Cancer statistics AJ. 2023. 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