A Novel Nanobody–Photosensitizer Conjugate for Hypoxia Resistant Photoimmunotherapy

Abstract As a non‐invasive treatment modality, photodynamic therapy has been a potential therapeutic method for metastatic and non‐metastatic tumors. In order to further improve the tumor selectivity, phtotoimmunotherapy (PIT) has been developed recently, which includes antibodies as the active targeting ligands. However, traditional monoclonal antibody‐based PIT suffers from long half‐lives and extended phototoxic side‐effects in vivo. Herein, a type I mechanism‐based photoimmunoconjugate (PIC) is developed by incorporating anti‐EGFR nanobody as the targeting ligand, and benzophenothiazine as the photosensitizer (PS). The small size and robust structure of the nanobody ensures excellent targeting accuracy and efficient renal excretion. Meanwhile, the type I PS is able to circularly transfer oxygen to superoxide radical upon irradiation to overcome hypoxia microenvironment. The PIC showed satisfying phototherapeutic ability both in normoxia and hypoxia, and displayed high selectivity towards tumor in vivo. By combining nanobody and Type I PS, the work presents a novel type of PIC for the precise treatment of tumors with high specificity and potency.