Programmed Synergistic Photochemotherapy and Immune Activation of Triple Negative Breast Cancer Using Anti-PD-L1 Antibody-Conjugated Multifunctional Nanocapsules

Zhiqiang Lin,1,* Hui Jiang,1,* Yingying Zhou,2 Li Xu,1 Lixin Jiang,1 Jing Du1 1Department of Ultrasound, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People’s Republic of China; 2Department of Ultrasound, Zhabei Central Hospital, Shanghai, 200070, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lixin Jiang, Email jinger_28@sina.com Jing Du, Email beautydujing@163.comPurpose: Triple-negative breast cancer (TNBC) is prone to relapse and metastasis due to the immunosuppressive state of the tumor microenvironment and limited exposure to relevant antigens, and chemotherapy alone has poor efficacy. We have developed a novel theranostic nanoplatform to address these problems: multifunctional nanocapsules (NCs) with a PD-L1-mediated gold shell induce immunogenic cell death (ICD) to remodel the immune microenvironment. PD-L1 and NLG919 dual immune checkpoints are programmed to synergistically sensitize photothermal therapy and chemotherapy, and photoacoustic imaging (PAI) is used to visualize and localize TNBC tissues for identification.Methods: DOX-NLG919@PLGA@Au-antiPD-L1 NCs (DNPA-aPD-L1 NCs) were prepared using an improved single emulsion water-in-oil (O/W) solvent evaporation method, electrostatic adsorption, gold seed surface-induced crystallization reduction method, and carbodiimide method. A series of animal models were established to focus on the in vivo PAI of NCs, the effects of photochemotherapy combined with immunotherapy and antitumor therapy, ICD induced by NCs, the metabolic distribution of NCs, and toxicity tests.Results: This project successfully constructed gold nanoshell-PLGA core NCs with PD-L1 antibody co-loaded with chemotherapeutic drugs doxorubicin and indoleamine 2,3-dioxygenase inhibitor NLG919. Laser-triggered release of DOX, NLG919, and photothermal therapy can synergistically induce immunogenic cell death (ICD), thereby enhancing tumor immunogenicity, inhibiting IDO, and reshaping the tumor immune microenvironment. This can effectively eliminate the primary TNBC lesions, inhibit recurrence and metastasis, significantly prolong the survival of tumor-bearing mice, and NCs have good in vivo biosafety. This diagnostic and therapeutic agent can be used for photochemotherapy, immunotherapy, and PAI to visualize and identify TNBC.Conclusion: The photochemotherapy mediated by the DNPA-aPD-L1 NCs we developed, combined with tumor microenvironment remodeling and immune activation, shows great promise for the diagnosis and treatment of TNBC.Keywords: triple-negative breast cancer, AuNPs, PD-L1 blockade, photochemotherapy, photoacoustic imaging