Multifunctional Protein Hybrid Nanoplatform for Synergetic Photodynamic‐Chemotherapy of Malignant Carcinoma by Homologous Targeting Combined with Oxygen Transport

Abstract Photodynamic therapy (PDT) under hypoxic conditions and drug resistance in chemotherapy are perplexing problems in anti‐tumor treatment. In addition, central nervous system neoplasm‐targeted nanoplatforms are urgently required. To address these issues, a new multi‐functional protein hybrid nanoplatform is designed, consisting of transferrin (TFR) as the multicategory solid tumor recognizer and hemoglobin for oxygen supply (ODP‐TH). This protein hybrid framework encapsulates the photosensitizer protoporphyrin IX (PpIX) and chemotherapeutic agent doxorubicin (Dox), which are attached by a glutathione‐responsive disulfide bond. Mechanistically, ODP‐TH crosses the blood–brain barrier (BBB) and specifically aggregated in hypoxic tumors via protein homology recognition. Oxygen and encapsulated drugs ultimately promote a therapeutic effect by down‐regulating the abundance of multidrug resistance gene 1 (MDR1) and hypoxia‐inducible factor‐1‐ α (HIF‐1 α ). The results reveal that ODP‐TH achieves oxygen transport and protein homology recognition in the hypoxic tumor occupation. Indeed, compared with traditional photodynamic chemotherapy, ODP‐TH achieves a more efficient tumor‐inhibiting effect. This study not only overcomes the hypoxia‐related inhibition in combination therapy by targeted oxygen transport but also achieves an effective treatment of multiple tumors, such as breast cancer and glioma, providing a new concept for the construction of a promising multi‐functional targeted and intensive anti‐tumor nanoplatform.