Li Jiansen, Cao Chen, Zhang Xinlu, Zhang Xu, Wang Sheng
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072, China.
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072, China.
Biomaterials. 2025 Jun;317:123106. doi: 10.1016/j.biomaterials.2025.123106. Epub 2025 Jan 11.
As a promising anti-tumor modality, photodynamic immunotherapy (PDIT) has been applied for the treatment of many solid tumors. However, tumor hypoxic condition and immunosuppressive microenvironment severely limit the treatment outcome of PDIT. Here, we have designed a hairpin tetrahedral DNA nanostructure (H-TDN)-modified bifunctional cascaded Pt single-atom nanozyme (PCFP@H-TDN) with encapsulation of the photosensitizer. The PCFP@H-TDN have dual enzyme-like activities, which can catalyze cascade reactions to generate sufficient O, reversing the tumor hypoxia and thereby significantly enhancing the anti-tumor effect of PDIT. Meanwhile, H-TDN can not only block the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) recognition pathway but also target the delivery of PD-L1 antisense oligonucleotides to reduce overall PD-L1 protein expression on the surface of tumor cells, achieving the combination of PD-1/PD-L1 pathway blockade and PD-L1 protein expression silencing. The dual-depressing PD-L1 significantly improves immune checkpoint blockade efficacy. In vivo studies have shown that the constructed PCFP@H-TDN synergistically improved the therapeutic effect of tumors in a multimodal manner through enhancing tumor immunogenicity and upregulating immune cell infiltration at the tumor site. This study provides an efficient nanomedicine to enhance PDIT by depressing PD-L1 and regulating hypoxia.
作为一种很有前景的抗肿瘤治疗方式，光动力免疫疗法（PDIT）已被应用于多种实体瘤的治疗。然而，肿瘤缺氧状态和免疫抑制微环境严重限制了PDIT的治疗效果。在此，我们设计了一种发夹状四面体DNA纳米结构（H-TDN）修饰的双功能级联铂单原子纳米酶（PCFP@H-TDN），并包裹了光敏剂。PCFP@H-TDN具有双酶样活性，可催化级联反应产生足够的氧气，逆转肿瘤缺氧，从而显著增强PDIT的抗肿瘤效果。同时，H-TDN不仅可以阻断程序性死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）识别途径，还可以靶向递送PD-L1反义寡核苷酸以降低肿瘤细胞表面的总体PD-L1蛋白表达，实现PD-1/PD-L1途径阻断与PD-L1蛋白表达沉默的联合。双重抑制PD-L1可显著提高免疫检查点阻断疗效。体内研究表明，构建的PCFP@H-TDN通过增强肿瘤免疫原性和上调肿瘤部位的免疫细胞浸润，以多模态方式协同提高了肿瘤的治疗效果。本研究提供了一种通过抑制PD-L1和调节缺氧来增强PDIT的高效纳米药物。
