Luo Yingnan, Wang Xueyuan, Li Yuting, Duan Dandan, Liu Keyao, Lei Meng, Zhang Liefeng, Zhu Yongqiang
School of Food and Pharmaceutical Engineering, Nanjing, Normal University, Nanjing 210023, China.
College of Life Science, Nanjing Normal University, Nanjing 210023, China.
Int J Biol Macromol. 2025 Jul;318(Pt 1):144962. doi: 10.1016/j.ijbiomac.2025.144962. Epub 2025 Jun 4.
Small interfering RNA targeting PD-L1 (siPD-L1) demonstrates therapeutic potential in cancer immunotherapy, but faces challenges including inefficient lysosomal escape and carrier-induced toxicity. To address these limitations, we developed a carrier-free nanoparticle (NP) system, TPP-Ce6@siPD-L1. The amino-modified triphenylphosphine (TPP) was covalently connected with Ce6 to form an amphiphilic complex, which then loaded siPD-L1 creating an efficient co-delivery system for photosensitizers (PS) and gene drugs. Electrostatic and hydrophobic interactions drove the spontaneous self-assembly of TPP-Ce6 and siPD-L1 into uniform spherical NPs with an average diameter of 190 ± 4.885 nm, achieving siPD-L1 encapsulation and Ce6 loading. These NPs exhibited excellent structural stability in serum over 5 days and rapid cellular uptake (internalization within 2 h), outperforming free siRNA. The mitochondrial targeting of TPP-Ce6 ensures the generation of reactive oxygen species (ROS) within tumor cell mitochondria upon light irradiation, leading to mitochondrial damage and apoptosis. Simultaneously, the delivery of siPD-L1 effectively silences PD-L1 expression, enhancing immune response through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway (cGAS-STING). This dual-modality platform integrates photodynamic therapy (PDT) and RNA interference (RNAi), offering a novel approach for synergistic anticancer therapy.
靶向程序性死亡配体1（PD-L1）的小干扰RNA（siPD-L1）在癌症免疫治疗中显示出治疗潜力，但面临包括溶酶体逃逸效率低下和载体诱导毒性等挑战。为了解决这些限制，我们开发了一种无载体纳米颗粒（NP）系统，即TPP-Ce6@siPD-L1。氨基修饰的三苯基膦（TPP）与Ce6共价连接形成两亲性复合物，然后负载siPD-L1，创建了一种用于光敏剂（PS）和基因药物的高效共递送系统。静电和疏水相互作用促使TPP-Ce6和siPD-L1自发自组装成平均直径为190±4.885nm的均匀球形NP，实现了siPD-L1的包封和Ce6的负载。这些NP在血清中5天内表现出优异的结构稳定性，并具有快速的细胞摄取能力（2小时内内化），优于游离siRNA。TPP-Ce6的线粒体靶向确保在光照射下肿瘤细胞线粒体内产生活性氧（ROS），导致线粒体损伤和凋亡。同时，siPD-L1的递送有效沉默PD-L1表达，通过环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激物（STING）途径（cGAS-STING）增强免疫反应。这种双模态平台整合了光动力疗法（PDT）和RNA干扰（RNAi），为协同抗癌治疗提供了一种新方法。
