STING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma

• Published in: Nature communications 2023-03, Vol.14 (1), p.1610-19, Article 1610
• Main Authors: Zhang, Peng, Rashidi, Aida, Zhao, Junfei, Silvers, Caylee, Wang, Hanxiang, Castro, Brandyn, Ellingwood, Abby, Han, Yu, Lopez-Rosas, Aurora, Zannikou, Markella, Dmello, Crismita, Levine, Rebecca, Xiao, Ting, Cordero, Alex, Sonabend, Adam M., Balyasnikova, Irina V., Lee-Chang, Catalina, Miska, Jason, Lesniak, Maciej S.
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 45/91; 631/250/251; 692/4028/67/1922; Agonists; Animal models; Animals; Antitumor activity; B7-H1 Antigen - metabolism; Brain; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - radiotherapy; Brain tumors; CD47 Antigen - metabolism; CD8 antigen; Cell activation; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - radiotherapy; Glioblastoma cells; Humanities and Social Sciences; Humans; Immune checkpoint; Immunity; Immunological memory; Immunology; Infiltration; Interferons; Irradiation; Lipids; Lymphocytes; Lymphocytes T; Metastases; Mice; multidisciplinary; Myeloid cells; Nanoparticles; Nanotechnology; PD-L1 protein; Phagocytes; Radiation therapy; Science; Science (multidisciplinary); Stimulators; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37328-9

As a key component of the standard of care for glioblastoma, radiotherapy induces several immune resistance mechanisms, such as upregulation of CD47 and PD-L1. Here, leveraging these radiotherapy-elicited processes, we generate a bridging-lipid nanoparticle (B-LNP) that engages tumor-associated myeloid cells (TAMCs) to glioblastoma cells via anti-CD47/PD-L1 dual ligation. We show that the engager B-LNPs block CD47 and PD-L1 and promote TAMC phagocytic activity. To enhance subsequent T cell recruitment and antitumor responses after tumor engulfment, the B-LNP was encapsulated with diABZI, a non-nucleotidyl agonist for stimulator of interferon genes. In vivo treatment with diABZI-loaded B-LNPs induced a transcriptomic and metabolic switch in TAMCs, turning these immunosuppressive cells into antitumor effectors, which induced T cell infiltration and activation in brain tumors. In preclinical murine models, B-LNP/diABZI administration synergized with radiotherapy to promote brain tumor regression and induce immunological memory against glioma. In summary, our study describes a nanotechnology-based approach that hijacks irradiation-triggered immune checkpoint molecules to boost potent and long-lasting antitumor immunity against glioblastoma. Glioblastoma is an immunologically cold tumour, with poor CD8 + T cell infiltration and enrichment in immunosuppressive tumour-associated myeloid cells. Here, the authors generate a bispecific lipid nanoparticle targeting CD47 and PD-L1, combined with a STING agonist, to promote anti-tumour immunity.