Hollow Cu2-xSe/PDA/IR820 Composite Nanoparticles with pH Response for Multimodal Synergistic Treatment of Esophageal Cancer

Purpose Esophageal cancer (EC) ranks among the most prevalent and lethal malignancies worldwide, and conventional therapeutic modalities, including surgery, radiotherapy, and chemotherapy, are constrained by inherent limitations. Recent advances in nanomedicine have opened new avenues for EC treatment. To achieve efficient and precise tumor eradication, this study developed a pH-responsive composite nanoplatform featuring a hollow architecture to enable high-efficiency loading of photosensitizers and realize multimodal synergistic therapy against EC through the integration of photothermal therapy (PTT), photodynamic therapy (PDT), and chemodynamic therapy (CDT).Methods A pH-responsive Cu2-xSe/PDA/IR820 composite nanoplatform was constructed by coating hollow Cu2-xSe nanoparticles with polydopamine PDA and loading the near-infrared photosensitizer IR820. Morphology, crystalline phase, elemental composition, and surface chemistry were characterized by TEM, XRD, XPS, and FT-IR. Photothermal conversion efficiency was quantified under 808 nm laser irradiation. IR820 release kinetics were monitored under different pH conditions of 5.0, 6.0, and 7.0 to assess pH-responsive behavior. In vitro studies on KYSE-150 EC cells included viability by CCK-8 assay, apoptosis by flow cytometry, ROS generation by DCFH-DA probe, mitochondrial membrane potential by JC-1 staining, and cellular uptake analysis. In vivo antitumor efficacy and biosafety were evaluated in an AKR tumor-bearing C57BL/6J mouse model via intratumoral injection and 808 nm laser irradiation, followed by tumor volume measurement, histopathological analysis with H&E, Ki-67, and TUNEL staining, and systemic toxicity assessment.Results The hollow Cu2-xSe/PDA/IR820 nanoparticles exhibited a uniform size of approximately 164 nm, excellent colloidal stability, and a high photothermal conversion efficiency of 44.56% under 808 nm laser irradiation. IR820 release displayed pronounced pH sensitivity, with a cumulative release of 23.07% at pH 5.0 within 30 minutes. In vitro, the nanoplatform combined with laser irradiation reduced KYSE-150 cell viability to 1.2% at 100 μg/mL, with an IC50 value of 18.74 μg/mL, induced 28.57% apoptosis, elevated intracellular ROS levels, decreased mitochondrial membrane potential, and depleted glutathione to 335 μmol/gprot. In vivo fluorescence imaging confirmed effective tumor accumulation via the EPR effect, with peak signal at 24 hours post-injection. Combined PTT/PDT/CDT treatment significantly suppressed tumor growth, reducing final tumor volume to 17.8% of the control group, and induced extensive apoptosis and necrosis in tumor tissues. Systemic biosafety evaluations revealed no significant hematological or histopathological abnormalities.Conclusion Hollow Cu2-xSe/PDA/IR820 composite nanoparticles loaded with IR820 were successfully fabricated and demonstrated remarkable advantages in multimodal combination therapy against EC.