【Angew.Chem.】南京邮电大学范曲立、尹超|通过谷胱甘肽触发重组加速分子内非辐射跃迁：可激活半导体聚合物纳米探针实现光热效率提升至78.67%与近红外二区精准诊疗
【Angew.Chem.】南京邮电大学范曲立、尹超|通过谷胱甘肽触发重组加速分子内非辐射跃迁：可激活半导体聚合物纳米探针实现光热效率提升至78.67%与近红外二区精准诊疗
文章标题：Accelerating Intramolecular Nonradiative Decay via GSH‐Triggered Reassembly of Semiconducting Polymer Nanoprobes for Activatable NIR‐II Phototheranostics 文章作者：Haotong Yin, Xiaofei Miao, Guangzhao Yang, Siyang Yu, Yuquan Ji, Yujing Zhang, Hui Zhou, Wenbo Hu, Ping Li, Chao Yin, Quli Fan 文章链接：https://doi.org/10.1002/anie.2537165
研发背景与关键科学问题
近红外二区（1000–1700 nm）可激活光声成像与光热治疗在深部病灶精准诊疗中具有重要应用前景，半导体聚合物纳米探针因优良的光学特性备受关注。然而，现有可激活近红外二区探针在构建上存在显著短板：传统策略通常需经由复杂繁琐的化学合成将响应基团共价引入疏水聚合物主链，导致响应位点易被包裹在纳米核心内部，极大削弱了在生物微环境中的响应灵敏度；且多数探针仅在近红外一区响应。为此，本研究旨在克服主链修饰合成繁琐及核心包埋导致的响应迟钝问题，探索一种通过外壳响应介导纳米重组的新机制，构建灵敏响应肿瘤微环境的高性能近红外二区诊疗一体化纳米探针。
Fig.1 Schematic diagram of the nanoprobe (SPN0) fabrication and the GSH-triggered activation mechanism. (a) The synthetic route of SP using DPP and TQ. (b) The preparation process of SPN0 and the illustration of GSH-triggered activation of NIR-II photoacoustic (PA) and photothermal (PT) signals for SPN0. SPNX represents the state of the nanoprobe at 6, 12, 18, or 24 h after GSH treatment, respectively. (c) Energy dissipation diagrams of excited states of SPN0 and SPN18. S0: ground state; S1: excited state; Abs.: absorption process.
纳米重组设计、激发态动力学机制与多级实验验证
研究设计了基于外层微环境响应性重组的闭环技术路线。本文首次提出的核心创新手段是将非响应性的“双受体”型近红外二区半导体聚合物（由二酮吡咯并吡咯与噻二唑并喹啉共聚而成）作为发色核心，通过纳米沉淀法将其封装于含二硫键的两亲性聚合物外壳中，构建出可激活纳米探针；当接触高浓度谷胱甘肽时，表面二硫键断裂引发纳米探针自发“变大重组”。飞秒瞬态吸收光谱揭示了其本质物理机制：重组引起的聚集加剧不仅通过缩短分子间距强化了分子间非辐射跃迁（约0.4皮秒超快寿命组分），更促进了骨架扭曲和骨架伸缩等低频振动，使分子内非辐射跃迁寿命从36.8皮秒显著缩短至7.3皮秒，二者协同加速非辐射衰变，进而大幅放大了光声与光热信号输出。
在实验验证方面，体系以不含二硫键的纳米探针为阴性对照基准，通过体外溶液测试、细胞模型（4T1乳腺癌细胞与AML12正常肝细胞）及荷瘤小鼠活体成像开展了系统评估。溶液实验表明，随谷胱甘肽孵育，探针平均水力学直径由45.7纳米逐渐增大至112.4纳米，光热转化效率从未激活状态的40.80%大幅跃升至78.67%，光声信号强度提升2.5倍（检测限为2.78微摩尔/升）。在细胞层面，癌细胞组在光照下升温达53.1摄氏度，细胞存活率显著抑制至25.7%（显著性检验）。活体双侧瘤与尾静脉给药实验进一步证实，注射12小时后肿瘤部位光声信号达到对照组的3.3倍，光热治疗使肿瘤区域在5分钟内升至50.6摄氏度并实现肿瘤完全抑制与消融，且主要脏器组织学检查未见异常，展现出优异的生物安全性。
此外，研究人员还将该重组响应策略拓展至基于噻二唑并苯并三唑、苯并双噻二唑等其他典型强拉电子受体单元构建的半导体聚合物体系，均验证了谷胱甘肽触发的近红外二区光声与光热协同增强效应；同时证明重组增大的纳米尺寸有助于延长纳米探针在肿瘤病灶内的滞留时间，强化诊疗闭环效果。
Fig.2 TEM and DLS results of SPN0 (a), SPN6 (b), SPN12 (c), SPN18 (d), and SPN24 (e). Bar: 200 nm. (f) Absorption spectra of all the SPNs.
Fig.3 (a) Photothermal images of all SPNs upon laser irradiation (1064 nm, 1.0 W/cm2) for 8 min. (b) The curves of temperature variation of all SPNs as a function of laser irradiation (1064 nm, 1.0 W/cm2) time. (c) NIR-II PAI (λex = 1064 nm) and the corresponding signal quantification results for all SPNs. The error bars represent the standard deviation of three separate measurements. (d–f) Pseudocolor fs-TA mapping of SPN0, SPN6, and SPN18 following photoexcitation at 1064 nm laser pulse. (g–i) fs-TA spectra of SPN0, SPN6, and SPN18 at selected decay times. (j) Kinetics traces and fitting lines of SPN0, SPN6, and SPN18 at the representative wavelength. (k) Schematic illustration of the excited state dynamics process of SPN0, SPN6, and SPN18.
Fig.4 Activatable NIR-II PAI and PTT toward cancer cells. (a) The NIR-II PAI (λex = 1064 nm) and signal quantification for AML12 only (i), 4T1 only (ii), AML12+SPN0 (iii), 4T1+SPN0 (iv), and 4T1+NEM+SPN0 (v). Statistical significance was determined using the T.TEST function (*** p < 0.001). The error bars represent the standard deviation of three separate measurements. (b) Photothermal images for various groups (i: AML12 only; ii: 4T1 only; iii: AML12+SPN0; iv: 4T1+SPN0; v: 4T1+NEM+SPN0). Cells were irradiated with 1064 nm laser (0.75 W/cm2) for 8 min. (c) Temperature changes of different groups (i: AML12 only; ii: 4T1 only; iii: AML12+SPN0; iv: 4T1+SPN0; v: 4T1+NEM+SPN0) upon NIR-II laser (1064 nm, 0.75 W/cm2) irradiation. (d) MTT assay of AML12 or 4T1 cells received various treatments. The error bars represent the standard deviation of five separate measurements. Flow cytometry (e) and live-dead staining (f) of 4T1 cells received different treatments (Control: without any treatments; SPN0: treated with SPN0 for 24 h; SPN0+L: treated with SPN0 for 18 h and then NIR-II laser irradiation; NEM+SPN0+L: pre-treated with NEM for 0.5 h and then SPN0 for 18 h, and subsequently NIR-II laser irradiation). After laser irradiation, cells were further incubated for 6 h, followed by flow cytometry analysis or live-dead staining.
Fig.5 Activatable NIR-II phototheranostics in vivo. The NIR-II PAI (a) and signal quantification (b) of 4T1 tumor-bearing mice simultaneously treated by intratumor injection (tumor) and subcutaneous injection (normal tissue) of SPN0 for 2 h. Statistical significance was determined using the T.TEST function (** p < 0.01). The error bars represent the standard deviation of three separate measurements. (c) Infrared thermal image of 4T1 tumor-bearing mice following concurrent intratumoral and subcutaneous injections of SPN0, with local irradiation (1064 nm, 1.0 W/cm2) applied to the respective sites for 4 min. (d) Temperature fluctuations of tumor and normal tissue from Figure 5c upon continuous laser irradiation (1064 nm, 1.0 W/cm2). (e) NIR-II PAI of 4T1 tumor-bearing mice after intravenous injection of SPN0 dispersion (1.5 mg/mL, 200 µL) at different time points. The red dotted circle indicated the tumor region. (f) The photoacoustic signal quantification of tumor from mice after intravenous injection of SPN0 dispersion (1.5 mg/mL, 200 µL) at different time points. The error bars represent the standard deviation of three separate measurements. Infrared thermal images of mice (g) and temperature changes of tumor (h) during PTT. Mice received laser irradiation (1064 nm, 1.0 W/cm2) at 12 h post-injection of PBS or SPN0. (i) Tumor volume changes of mice received different treatments during 2 weeks. Statistical significance was determined using the T.TEST function (*** p < 0.001). The error bars represent the standard deviation of five separate measurements. (j) Photographs of tumors excised from mice at day 14 after various treatments. (k) The histological examination of tumors excised from mice received different treatments.
机制创新与诊疗性能多维提升
本文的核心创新在于打破了依赖繁琐主链共价修饰的传统模式，开创了利用表面基质响应性重组调控激发态分子内与分子间非辐射跃迁动力学的新策略。该方案将探针光热转化效率从40.80%提升至78.67%，使肿瘤与正常组织的光声对比度提升1.97倍，并在体内实现3.3倍的信号特异性放大，完美解决了深部病灶成像响应迟钝、合成路径繁琐及背景干扰高的痛点；该设计理念通过更换外壳可裂解连接键，可灵活拓展至其他生物标志物激活系统，为模块化开发下一代近红外二区精准纳米药物提供了通用范式。
文章分享
如果这篇文章对你有帮助，欢迎分享给更多人！