Sun Shi, Wang Rui, Mu Xue-Lu-Er, Feng Wen-Bi, Kong Hao, Li Ya-Jie, Gao Min, Lu Ying-Xi, Sun Hui-Rui, Zhou Xian-Feng
College of Material Science and Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.
College of Polymer Science and Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.
Acta Pharmacol Sin. 2025 Jul 25. doi: 10.1038/s41401-025-01609-4.
Prodrugs usually convert into active compounds within cells via endogenous or external stimuli to improve the diagnostic accuracy and therapeutic efficacy, but this singular release profile often fails to meet the multifunctional needs of cancer therapeutics. In this study we proposed a strategy of "nanostructural conversion at nano-bio interface" and constructed a small-molecule nanoprodrug (APO-S-Cy7-TCF) for multifunctional anti-tumor phototheranostics. Upon exposure to redox biomolecules (ROS/GSH) in tumor microenvironment, the pristine nanostructure of APO-S-Cy7-TCF disassembled, releasing Cy7-TCF-OH and APO that interacted with heat shock proteins to initiate apoptosis. Cy7-TCF-OH could then re-assemble into smaller nanosaucers with enhanced photothermal properties and self-augmented ROS-generating capacity, enabling synergistic phototherapy for tumor ablation. In particular, Cy7-TCF-OH nanosaucers were long retained in residual tumors and could further interact with albumin to form smaller Cy7-TCF-OH@albumin nanocomposites that time-dependently activated near-infrared fluorescence for prognostic assessment. Using these biomolecule-derived elements to program supramolecular sequential structural conversions at nano-bio interface, our study establishes a new way for small-molecule-based multifunctional phototheranostic platform.
前药通常通过内源性或外源性刺激在细胞内转化为活性化合物，以提高诊断准确性和治疗效果，但这种单一的释放模式往往无法满足癌症治疗的多功能需求。在本研究中，我们提出了一种“纳米生物界面的纳米结构转化”策略，并构建了一种用于多功能抗肿瘤光热诊疗的小分子纳米前药（APO-S-Cy7-TCF）。在肿瘤微环境中暴露于氧化还原生物分子（ROS/GSH）后，APO-S-Cy7-TCF的原始纳米结构解体，释放出Cy7-TCF-OH和APO，它们与热休克蛋白相互作用引发细胞凋亡。然后，Cy7-TCF-OH可以重新组装成具有增强光热性能和自增强ROS生成能力的更小的纳米碟，实现协同光疗以消融肿瘤。特别地，Cy7-TCF-OH纳米碟长期保留在残留肿瘤中，并可进一步与白蛋白相互作用形成更小的Cy7-TCF-OH@白蛋白纳米复合材料，其随时间激活近红外荧光用于预后评估。利用这些生物分子衍生的元素在纳米生物界面上设计超分子顺序结构转化，我们的研究为基于小分子的多功能光热诊疗平台建立了一种新方法。
