STING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma.
Peng ZhangAida RashidiJunfei ZhaoCaylee SilversHanxiang WangBrandyn CastroAbby EllingwoodYu HanAurora Lopez-RosasMarkella ZannikouCrismita DmelloRebecca LevineTing XiaoAlex CorderoAdam M SonabendIrina V BalyasnikovaCatalina Lee-ChangJason M MiskaMaciej S LesniakPublished in: Nature communications (2023)
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.
Keyphrases
- induced apoptosis
- early stage
- cell cycle arrest
- locally advanced
- radiation induced
- radiation therapy
- healthcare
- drug delivery
- cancer therapy
- palliative care
- high glucose
- bone marrow
- nk cells
- drug induced
- squamous cell carcinoma
- stem cells
- diabetic rats
- single cell
- rectal cancer
- fatty acid
- immune response
- poor prognosis
- anti inflammatory