Self-Assembly Catalase Nanocomplex Conveyed by Bacterial Vesicles for Oxygenated Photodynamic Therapy and Tumor Immunotherapy

Abstract

Jiayu Zhang,1,* Zinan Li,2,* Ling Liu,3 Longyun Li,2 Lu Zhang,2 Yongkun Wang,4 Jia Zhao2 1Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 3Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 4Department of Orthopedic, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia Zhao, Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China, Email [email protected] Yongkun Wang, Department of Orthopedic, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China, Email [email protected]: Photodynamic therapy (PDT) is an effective therapeutic modality that has been extensively studied in treatment of various cancers. However, issues with inadequate oxygen (O2) concentration in tumor tissue and inadequate immune response generation have hindered its successful application in tumor therapy.Methods: Firstly, the self-assembly nanocomplex (CAT-Ce6), which is composed of hydrophilic catalase and hydrophobic photosensitizer Chlorin e6 (Ce6), was fabricated to support oxygenated PDT. Secondly, for supplying PDT with enhanced antitumoral immunity, CAT-Ce6 was coated with PD-L1 antibody modified-attenuated Salmonella outer membrane vesicles (OMV-aPDL1). Finally, the catalytic activity, tumor targeting, hypoxia ameliorating, immune effect initiating and anti-tumor capacities of the integral nanosystem CAT-Ce6@OMV-aPDL1 were evaluated systematically.Results: The self-assembly nanocomplex (CAT-Ce6) generated sufficient O2 and promoted the solubility of Ce6 simultaneously, which enhanced PDT significantly. OMV-aPDL1 inherited most of the immunogenic membrane-associated components from the parent bacteria, possessing immunomodulation ability for immunosuppressive tumor microenvironment reprogramming and reducing immune escape. The obtained nanosystem CAT-Ce6@OMV-aPDL1 durably relieved hypoxia, resulting in amplifying PDT-mediated cytotoxicity to generate a pool of tumor-associated antigens, stimulating anti-tumor immune responses and even inducing an immune memory effect, which inhibited tumor development efficiently.Conclusion: The resultant CAT-Ce6@OMV-aPDL1 displays excellent efficacy of PDT and immunotherapy to achieve antitumor effects, which provides a new avenue for combinatorial therapy against various cancers.Keywords: oxygenated photodynamic therapy, anti-tumor immune response, long term hypoxia relieving, immune memory effect

Keywords

• oxygenated photodynamic therapy
• anti-tumor immune response
• long term hypoxia relieving
• immune memory effect