Microalgae-based drug delivery system for tumor microenvironment photo-modulating and synergistic chemo-photodynamic therapy of osteosarcoma

Osteosarcoma (OS) is one of the most common malignant tumors in children and young adults. As chemotherapy and other therapies are limited by low therapeutic efficiency, severe side effects and single therapeutic function, it is of high value to develop innovative therapies for precise and efficient treatment of OS. Herein, natural photosynthetic microalgae (C. vulgaris, CV) were utilized as carriers for the chemotherapeutic agent doxorubicin (DOX) to create a multifunctional therapeutic platform (CV@DOX) for the photo-modulation of the tumor microenvironment (TME) and synergistic chemo-photodynamic therapy of osteosarcoma. CV@DOX exhibited rapid drug release behavior in the acidic TME, improving the efficiency of chemotherapy against tumors and reducing side effects on other normal tissues. Under 650 nm laser irradiation, CV@DOX demonstrated the ability to effectively generate oxygen to alleviate tumor hypoxia and utilize the photosensitizing properties of chlorophyll in CV to produce an increased amount of reactive oxygen species (ROS), thereby enhancing photodynamic therapy (PDT). CV@DOX-mediated synergistic chemo-photodynamic therapy demonstrated efficacy in halting tumor progression in an orthotopic osteosarcoma mouse model by promoting tumor cell apoptosis, inhibiting tumor proliferation and angiogenesis. Moreover, chlorophyll-assisted fluorescence imaging enabled monitoring of the distribution of CV@DOX in osteosarcoma after administration. Finally, CV@DOX did not cause significant hematological and tissue toxicity, and prevented DOX-induced cardiotoxicity, showing good in vivo biocompatibility. Overall, this work presents a novel TME-responsive and TME-modulating platform for imaging-guided multimodal osteosarcoma treatment.