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
Department of Radiation Oncology, Stanford University, Stanford, CA, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
Nat Biotechnol. 2024 Oct 24. doi: 10.1038/s41587-024-02448-0.
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) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSC 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 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）在原发性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。在此，我们报告了一种可代谢的二元超簇（BSC），它将作为放射增敏佐剂的金纳米簇与靶向免疫抑制介质半乳凝素-1（Gal-1）的小干扰RNA（siRNA）相结合。BSC由在聚合物基质中可逆交联的阳离子金纳米簇和siRNA复合物组成，该聚合物基质在数周内可生物降解，有助于清除（4周时体内清除率达90.3%）以降低毒性。远高于肾滤过阈值的粒径有助于被动递送至肿瘤。利用头颈癌小鼠模型，我们表明BSC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体，增强了SABR在原发性和转移性肿瘤中的放射动力学和免疫治疗效果。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，将局部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。
