Li Meirong, Yang Jingyu, Yao Xinhuang, Li Xiang, Xu Zhourui, Tang Shiqi, Sun Bangxu, Lin Suxia, Yang Chengbin, Liu Jia
School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
Central Laboratory of The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen 518172, China.
Pharmaceutics. 2023 Mar 6;15(3):854. doi: 10.3390/pharmaceutics15030854.
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths in the world. It is urgent to search for safe and effective therapies to address the CRC crisis. The siRNA-based RNA interference targeted silencing of PD-L1 has extensive potential in CRC treatment but is limited by the lack of efficient delivery vectors. In this work, the novel cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs)/siPD-L1 co-delivery vectors AuNRs@MS/CpG ODN@PEG-bPEI (ASCP) were successfully prepared by two-step surface modification of CpG ODNs-loading and polyethylene glycol-branched polyethyleneimine-coating around mesoporous silica-coated gold nanorods. ASCP promoted dendritic cells (DCs) maturation by delivering CpG ODNs, exhibiting excellent biosafety. Next, mild photothermal therapy (MPTT) mediated by ASCP killed tumor cells and released tumor-associated antigens, further promoting DC maturation. Furthermore, ASCP exhibited mild photothermal heating-enhanced performance as gene vectors, resulting in an increased PD-L1 gene silencing effect. Enhanced DCs maturity and enhanced PD-L1 gene silencing significantly promoted the anti-tumor immune response. Finally, the combination of MPTT and mild photothermal heating-enhanced gene/immunotherapy effectively killed MC38 cells, leading to strong inhibition of CRC. Overall, this work provided new insights into the design of mild photothermal/gene/immune synergies for tumor therapy and may contribute to translational nanomedicine for CRC treatment.
结直肠癌（CRC）是全球第三大常见癌症，也是全球癌症相关死亡的第二大主要原因。寻找安全有效的治疗方法来应对CRC危机迫在眉睫。基于小干扰RNA（siRNA）的RNA干扰靶向沉默程序性死亡配体1（PD-L1）在CRC治疗中具有广泛潜力，但受到缺乏高效递送载体的限制。在这项工作中，通过在介孔二氧化硅包覆的金纳米棒周围进行两步表面修饰，即加载胞嘧啶-磷酸-鸟嘌呤寡脱氧核苷酸（CpG ODNs）和聚乙二醇-支化聚乙烯亚胺涂层，成功制备了新型的CpG ODNs/siPD-L1共递送载体金纳米棒@介孔二氧化硅/CpG ODN@聚乙二醇-b-聚乙烯亚胺（ASCP）。ASCP通过递送CpG ODNs促进树突状细胞（DCs）成熟，表现出优异的生物安全性。接下来，由ASCP介导的温和光热疗法（MPTT）杀死肿瘤细胞并释放肿瘤相关抗原，进一步促进DC成熟。此外，ASCP作为基因载体表现出温和光热增强性能，导致PD-L1基因沉默效果增强。增强的DC成熟度和增强的PD-L1基因沉默显著促进了抗肿瘤免疫反应。最后，MPTT与温和光热增强基因/免疫疗法的联合有效地杀死了MC38细胞，导致对CRC的强烈抑制。总体而言，这项工作为肿瘤治疗的温和光热/基因/免疫协同设计提供了新的见解，并可能有助于CRC治疗的转化纳米医学。
