Overcoming Photodynamic Therapy Resistance: GSH-Responsive AIE Photosensitizer-Hydroxycamptothecin Nanoliposomes for Extrahepatic Cholangiocarcinoma.

Photodynamic therapy (PDT) has been shown to improve survival and quality of life in patients with unresectable extrahepatic cholangiocarcinoma. However, its therapeutic efficacy is frequently limited by the survival of residual tumor cells that can re-enter the proliferative cycle. Our previous studies showed that residual cholangiocarcinoma cells can re-enter the proliferative cycle following PDT accompanied by hypoxia-induced activation of the HIF-1α survival pathway and intracellular antioxidant programs. To address this residual viability, we developed a glutathione-responsive targeted nanosystem (TSH NPs), in which the aggregation-induced emission (AIE) photosensitizer TPA-Ph-RDN 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-1α-mediated hypoxic adaptation pathway, thereby reducing residual tumor viability and enhancing PDT efficacy. This strategy achieves a dual-mechanism, two-pronged 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.