A self-delivery albumin nanomedicine amplified photodynamic therapy against esophageal cancer through COX-2/PGE2 interruption and regulation of mitochondrial respiratory

Photodynamic therapy (PDT) has emerged as a promising non-invasive cancer treatment due to its selective tumor ablation and excellent safety characteristics. However, its efficacy is limited by tumor hypoxia and excessive inflammation. In this study, we fabricated human serum albumin-based nanoparticles (CAI NPs) encapsulating celecoxib (CXB), atovaquone (ATO), and IR820 <i>via</i> sonication. The CAI NPs exhibited favorable physicochemical properties, including a uniform size distribution (<200 nm), high encapsulation efficiency and excellent colloidal stability. Initially, ATO acts as a mitochondrial complex III inhibitor, suppressing oxidative phosphorylation to ameliorate tumor hypoxia. This hypoxia alleviation potentiates PDT efficacy by enhancing tumor cell ROS generation. Furthermore, concomitant COX-2/PGE2 inhibition by CXB attenuates the excessive inflammatory cascade triggered during PDT, resulting in enhanced therapeutic outcomes through microenvironment modulation. Eventually, the dual-enhanced CAI NPs demonstrate potent antitumor activity in both <i>in vivo</i> and <i>ex vivo</i> models, while maintaining excellent biocompatibility under physiological conditions. In summary, the integrated three-drug regimen conclusively enhances photodynamic therapeutic outcomes through multimodal mechanisms, establishing a viable treatment approach for esophageal cancer.