Strategies to enhance the anti-tumor immune response of stereotactic ablative radiotherapy (SABR) at primary tumors and abscopal sites are under intensive investigation. Here we report a metabolizable binary supracluster (BSC_gal) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSC_gal comprises reversibly crosslinked cationic gold nanoclusters and siRNA complexes in a polymer matrix that biodegrades over weeks, facilitating clearance (90.3% in vivo clearance at 4 weeks) to reduce toxicity. The particle size well above the renal filtration threshold facilitates passive delivery to tumors. Using mouse models of head and neck cancer, we show that BSC_gal augments the radiodynamic and immunotherapeutic effects of SABR at the primary and metastatic tumors by promoting tumor-inhibitory leukocytes, upregulating cytotoxic granzyme B and reducing immunosuppressive cell populations. It outperforms SABR plus Gal-1 antagonists, chemoradiation drug cisplatin or PD-1 inhibitor. This work presents a translatable strategy to converge focal radiosensitization with targeted immune checkpoint silencing for personalized radioimmunotherapy.

增强立体定向消融放疗 （SABR） 在原发肿瘤和远隔部位的抗肿瘤免疫反应的策略正在深入研究中。在这里，我们报道了一种可代谢的二元超簇 （BSC_gal），它将金纳米簇作为放射增敏佐剂与靶向免疫抑制介质半乳糖凝集素-1 （Gal-1） 的小干扰 RNA （siRNA） 相结合。BSC_gal 由聚合物基质中的可逆交联阳离子金纳米簇和 siRNA 复合物组成，可在数周内生物降解，促进清除（4 周时体内清除率为 90.3%）以降低毒性。远高于肾滤过阈值的粒径有助于被动输送到肿瘤。使用头颈癌小鼠模型，我们表明 BSC_gal 通过促进肿瘤抑制性白细胞、上调细胞毒性颗粒酶 B 和减少免疫抑制细胞群来增强 SABR 对原发性和转移性肿瘤的放射动力学和免疫治疗作用。它优于 SABR 加 Gal-1 拮抗剂、放化疗药物顺铂或 PD-1 抑制剂。这项工作提出了一种可转化的策略，将局灶性放射增敏与靶向免疫检查点沉默相结合，以实现个性化放射免疫治疗。