Abstract

Transarterial radioembolization (TARE) with β-emitting radionuclides is widely used for hepatocellular carcinoma (HCC), but its clinical efficacy remains to be further improved. α-particle-emitting radionuclides possess high linear energy transfer (LET) and unique advantages in cancer therapy, motivating α-particle based composite platform. Accordingly, we engineer the first clinically mimetic α-TARE microsphere by in-situ ²²³Ra-doped calcium-alginate composite microsphere (²²³Ra/Ca-ALG MS) using a hydrogel matrix, in which alginate "egg-box" coordination captures Ra²⁺ to provide stable radiolabeling, delivered via selective hepatic arterial injection to HCC. The microspheres exhibited excellent radiolabeling stability (88% retention after 384 h) and potent, dose-dependent cytotoxicity against HCC cells under hypoxia. In an orthotopic rat HCC model, 223 Ra/Ca-ALG MS-based TARE achieves precise intratumoral localization and sustained retention on SPECT/CT; ¹⁸F-FDG PET/CT and histopathology indicate a robust antitumor response, while serum biochemistry and histology support a favorable safety profile. Moreover, ²²³Ra/Ca-ALG MS provide powerful immune-activating capacity. Transcriptomics reveals activation of DNA-damage response, immunogenic cell death, and antigen-presentation pathways, flow cytometry and immunohistochemistry show increased dendritic-cell maturation and CD8⁺ T-cell infiltration. Collectively, 223 Ra/Ca-ALG MS demonstrates hypoxia-tolerant cytotoxicity, immune-activating potential, offering new insights for the development of immune-based TARE strategies in HCC and showing promising prospects for clinical translation.