【JACS】港中深唐本忠院士、内蒙古大学王建国|荧光增强50.8倍、抑瘤率95%：全氟阴离子让阴离子-π⁺光敏剂同时触发坏死性凋亡与铁死亡#

文章标题：Perfluoroalkyl Anion Strategy to Construct Anion–π⁺ Type NIR-II Phototheranostic Agents for Enhanced Tumor Immunotherapy via Necroptosis/Ferroptosis 文章作者：Lingxiu Liu, Xue Wang, Jianye Gong, Ying Zhang, Guoyu Jiang, Ben Zhong Tang, Jianguo Wang 文章链接：Journal of the American Chemical Society

为什么换的是阴离子#

实体瘤免疫治疗受制于免疫抑制微环境，NIR-II光动力治疗能通过免疫原性细胞死亡（ICD）增强免疫应答，但现有阴离子-π⁺型光敏剂多只改造π⁺核心，阴离子常被当作无关反离子。本文要回答的是：把六氟锑酸根（HFA）换成单侧或双侧全氟烷基阴离子，能否同时提高荧光、活性氧（ROS）生成和非凋亡免疫原性死亡。

Figure 1.(a) Perfluoroalkyl anion strategy for enhancing fluorescence intensity and ROS generation performance. (b) Necroptosis and ferroptosis activate powerful immune, suppressing primary tumors and lung metastasis (Created by Figdraw).

荧光和ROS怎么被拉高#

作者合成A/HFA和TPQ/HFA，再用全氟丁基磺酸根（PFB）和双（全氟丁基磺酰）亚胺根（BPFB）做离子交换，得到A/PFB、TPQ/PFB、A/BPFB、TPQ/BPFB。等温滴定量热显示BPFB与TPQ/HFA结合更强，解离常数3.41×10⁻⁶ M；分子动力学给出BPFB与π⁺核心的范德华作用能**−13800 kJ mol⁻¹**，明显强于PFB和HFA。纳米颗粒中，A/BPFB NPs荧光比A/HFA NPs强50.8倍，TPQ/BPFB NPs比TPQ/HFA NPs强4.2倍；TPQ/BPFB NPs在约1040 nm发NIR-II光，660 nm照射下主要产生O₂•⁻和•OH，属I型ROS，并显示线粒体靶向和抗光漂白。细胞层面，TPQ/BPFB NPs光照后引起RIPK1/RIPK3/MLKL磷酸化升高、GPX4下降、GSH耗竭，同时释放ATP、CRT和HMGB1，说明坏死性凋亡和铁死亡被同时激活。小鼠瘤内注射加660 nm光照，抑瘤率95%，脾脏成熟DC比例46.9%，CD4⁺和CD8⁺T细胞分别达17.1% 和13.5%，肺转移生物发光降至对照的7%。这些结果依赖瘤内注射、单一种肿瘤模型和有限样本量，原文未验证系统给药、深部肿瘤和长期安全性。

Figure 2.(a) Absorption spectra and (b) photoluminescence (PL) spectra of A/HFA, A/PFB, and A/BPFB in PBS. (c) Absorption spectra and (d) PL spectra of TPQ/HFA, TPQ/PFB, and TPQ/BPFB in PBS. Isothermal titration calorimetry data for the titration of (e-f) PFB anion or (g-h) BPFB anion with TPQ/HFA at 25 °C. (i) Molecular dynamics simulation of 100 BPFB anions and 100 π+ core forming a compact structure. (j) Time-dependent van der Waals interaction energy between anions (HFA, PFB, and BPFB) and π+ core. (k) Time-dependent van der Waals interaction energy between anions (HFA, PFB, and BPFB) and sulfur-containing aromatic rings in π+ core. (l) Time-dependent variation in mean square displacement (MSD).

Figure 8.(a) Treatment schedule of TPQ/HFA NPs and TPQ/BPFB NPs-mediated therapy against lung metastasis. (b) The luciferase signal of 4T1-Luc cells detected to track the growth of lung metastasis in different groups. (c) Intensity analysis of the luciferase signal in the lungs in Figure 8b. Data were presented as mean ± SD derived from n = 4 samples per group, * p < 0.05. (d) Representative images of the tumor lung metastasis sections examined by H&E staining. Scale bars = 1000 μm.

能用到哪一步#

这项工作把“阴离子工程”变成可操作的调控手段，给NIR-II光免疫治疗提供了一条不改变π⁺核心就能增强荧光和I型ROS的路径。对光敏剂开发者，它提示反离子不是旁观者；但临床转化仍需系统给药、更大动物模型和长期毒性数据，原文未提供直接转化证据。它更像一个机制清晰的先导设计，而不是已经可用的治疗方案。