美国斯坦福大学Quynh-Thu Le团队近期取得重要工作进展，他们研究发现，纳米金颗粒与siRNA组成的二元超簇复合物可增强原发性和转移性肿瘤立体定向消融放疗的抗肿瘤免疫反应。相关研究成果2024年10月24日在线发表于《自然—生物技术》杂志上。

据介绍，增强立体定向消融放疗（SABR）在原发性肿瘤和体外肿瘤部位的抗肿瘤免疫反应的策略正在深入研究中。

研究人员报告了一种可代谢的二元超簇（BSC_gal），它将作为放射增敏佐剂的金纳米簇与靶向免疫抑制介质Gal-1的siRNA结合在一起。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。

粒径远高于肾过滤阈值有助于被动递送至肿瘤。使用癌症小鼠模型，研究人员发现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，增强了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。

总之，这一研究提出了一种可翻译的策略，将局灶性放射增敏与靶向免疫检查点沉默相结合，用于个性化放射免疫治疗。

附：英文原文

Title: Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors

Author: Jiang, Yuyan, Cao, Hongbin, Deng, Huaping, Guan, Li, Langthasa, Jimpi, Colburg, Deana Rae Crystal, Melemenidis, Stavros, Cotton, Renee M., Aleman, John, Wang, Xiao-Jing, Graves, Edward E., Kalbasi, Anusha, Pu, Kanyi, Rao, Jianghong, Le, Quynh-Thu

Issue&Volume: 2024-10-24

Abstract: 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 (BSCgal) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSCgal 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 4weeks) 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 BSCgal 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.

DOI: 10.1038/s41587-024-02448-0

Source: https://www.nature.com/articles/s41587-024-02448-0