Systemic tumor eradication by single-modality immunogenic neutron radiotherapy via size-controlled boron-10-enriched...

Photon-based radiotherapy is a mainstay of cancer treatment but rarely induces systemic tumor rejection alone. Boron neutron capture therapy (BNCT) is a promising alternative consisting of neutron radiation and boron drug administration. However, systemic antitumor response by BNCT typically requires additional immunomodulator and high boron drug dosages, raising safety concerns. Herein, we develop a low-dose nanoparticle (NP)-mediated immunogenic neutron radiotherapy to eradicate tumor systemically without external immunomodulator. To realize this, we synthesize poly(glycerol)-functionalized boron-10 carbide NPs with 50 nm size (¹⁰B₄C(50)-PG), which exhibit superior tumor targeting and retention properties to the other sizes we evaluated. Upon neutron irradiation, ¹⁰B₄C(50)-PG achieves efficient tumor eradication or suppression across various murine tumor models at a lower dosage (12 mg kg^-1) as compared with most of the boron drugs including the clinically approved boronophenylalanine (500 mg kg^-1). Moreover, antitumor immunity is boosted after BNCT in multiple tumor models to elicit abscopal effect treating both neutron-irradiated and non-irradiated tumors, and immune-memory preventing tumor recurrence. Additionally, minimal side effects are observed in one-year safety study. Overall, our finding demonstrates ¹⁰B₄C(50)-PG-BNCT for systemic tumor rejection, which may address the limitation of radiotherapy to elicit systemic antitumor immunity with a favorable safety profile. Moreover, this study identifies NP size as a key parameter for improving tumor delivery efficacy of boron drugs, enhancing BNCT-induced antitumor immunity.