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However, its therapeutic efficacy is frequently limited by the survival of residual tumor cells that can re\u2010enter the proliferative cycle. Our previous studies showed that residual cholangiocarcinoma cells can re\u2010enter the proliferative cycle following PDT accompanied by hypoxia\u2010induced activation of the HIF\u20101\u03b1 survival pathway and intracellular antioxidant programs. To address this residual viability, we developed a glutathione\u2010responsive targeted nanosystem (TSH NPs), in which the aggregation\u2010induced emission (AIE) photosensitizer TPA\u2010Ph\u2010RDN is conjugated to the chemotherapeutic agent hydroxycamptothecin (HCPT) via a disulfide linkage. This design enables HCPT to exert direct cytotoxic effects while simultaneously suppressing the HIF\u20101\u03b1\u2010mediated hypoxic adaptation pathway, thereby reducing residual tumor viability and enhancing PDT efficacy. This strategy achieves a dual\u2010mechanism, two\u2010pronged therapeutic effect. Both in vitro and in vivo studies demonstrated that TSH NPs elicited markedly synergistic antitumor activity, highlighting their potential as a promising therapeutic approach for improving clinical outcomes in patients with eCCA.<\/jats:p>","DOI":"10.1002\/adhm.71599","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T04:55:07Z","timestamp":1786683307000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Overcoming Photodynamic Therapy Resistance: GSH\u2010Responsive AIE Photosensitizer\u2010Hydroxycamptothecin Nanoliposomes for Extrahepatic Cholangiocarcinoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Yong","family":"Qu","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Department of Emergency Surgery Union Hospital Tongji Medical 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