A PD-L1 siRNA-Loaded Boron Nanoparticle for Targeted Cancer Radiotherapy and Immunotherapy

Abstract

Although the combination of radiotherapy and immunotherapy is regarded as a promising clinical treatment strategy, numerous clinical trials have failed to demonstrate synergistic effects. One of the key reasons is that conventional radiotherapies inevitably damage intratumoral effector immune cells. Boron Neutron Capture Therapy (BNCT) is a precise radiotherapy that selectively kills tumor cells while sparing adjacent normal cells, by utilizing ¹⁰B agents and neutron irradiation. Therefore, combinational BNCT-immunotherapy holds promise for achieving more effective synergistic effects. Here it develops a ¹⁰B-containing polymer that self-assembled with PD-L1 siRNA to form ¹⁰B/siPD-L1 nanoparticles for combinational BNCT-immunotherapy. Unlike antibodies, PD-L1 siRNA can inhibit intracellular PD-L1 upregulated by BNCT, activating T-cell immunity while also suppressing DNA repair. This can enhance BNCT-induced DNA damage, promoting immunogenic cell death (ICD) and further amplifying the antitumor immune effect. The results demonstrated that BNCT using ¹⁰B/siPD-L1 nanoparticles precisely killed tumor cells while sparing adjacent T cells and induced a potent antitumor immune response, inhibiting distal and metastatic tumors.

Keywords: PD‐L1; boron neutron capture therapy (BNCT); immunotherapy; nanoparticle; radiotherapy; siRNA.