上海交通大学窦晓秋团队报道了喜树碱手性纳米纤维触发焦亡增强免疫治疗。相关研究成果于2025年1月13日发表在《德国应用化学》。

喜树碱（CPT）是一种化学治疗剂，在癌症治疗中显示出显著的潜力。然而，作为一种药物，CPT分子的水溶性较差，生物利用度有限，免疫反应不足。

该文中，研究人员通过超分子自组装构建了具有右手手性性质的CPT纳米纤维（CNF），这显著克服了与生物利用度相关的溶解度障碍，改善了肿瘤免疫预后。CNF在pH 6.5条件下表现出较高的手性不对称因子（gabs）（~0.11）和显著的结构稳定性。

通过与线粒体靶向DSPE-PEG-TPP配制手性CNF，CNF在癌症细胞的线粒体中特异性积累，导致线粒体功能障碍，与CPT分子相比，活性氧（ROS）的产生增加3.42倍。

这种ROS扩增激活了caspase-1/gasdermin D（GSDMD）通路，诱导焦亡，促进M1巨噬细胞极化，增强CD8+T细胞依赖性抗肿瘤免疫。因此，与CPT分子相比，CNF对远端肿瘤的生长抑制作用提高了1.8倍，并减少了肿瘤转移。

该创新平台将CPT分子组装成手性CNF结构，有望克服CPT分子目前的临床局限性，为下一代免疫治疗策略的发展提供新的方向。

附：英文原文

Title: Chiral Nanofibers of Camptothecin Trigger Pyroptosis for Enhanced Immunotherapy

Author: Chuan Liang Feng, Fengli Gao, Xiaxin Qiu, Sravan Baddi, Sijia He, Shuting Wang, Changli Zhao, Xiaoqiu Dou

Issue&Volume: 2025-01-13

Abstract: Abstract: Camptothecin (CPT), a chemotherapeutic agent, demonstrates significant potential in cancer therapy. However, as a drug, CPT molecule suffers from poor water solubility, limited bioavailability, and insufficient immune response. Herein, we construct CPT nanofibers (CNF) with a right-handed chiral property via supramolecular self-assembly, which significantly overcomes the solubility barriers associated with bioavailability and improves tumor immune prognosis. The CNF exhibits high chiral asymmetry factor (gabs) (~ 0.11) and remarkable structure stability under pH 6.5 condition. By formulating chiral CNF with mitochondrial-targeted DSPE-PEG-TPP, CNF accumulates specifically in the mitochondria of cancer cells, leading to mitochondrial dysfunction and a 3.42-fold increase in reactive oxygen species (ROS) generation compared to the CPT molecule. This ROS amplification activates the caspase-1/gasdermin D (GSDMD) pathway, inducing pyroptosis that promotes M1 macrophage polarization and enhences CD8+ T-cell-dependent antitumor immunity. Consequently, CNF achieves 1.8-fold greater growth inhibition of distant tumor and reduces tumor metastasis compared to the CPT molecule. Our innovative platform, assembling CPT molecules into chiral CNF structure, is highly anticipated to overcome the current clinical limitations of CPT molecules and offer a new direction for the development of next-generation immunotherapy strategies.

DOI: 10.1002/anie.202423446

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202423446