设计先进的载体，实现时间或刺激调控的药物释放，对于提高肿瘤治疗效果具有巨大潜力。本文中，设计了适用于结直肠肿瘤的透明质酸（HA）包被的脂质体，以有效传递多靶向多细胞器和ALP/GSH双响应的前药进行组合治疗。在该系统（命名为CPTP/RA-HALipo）中，通过二硫键连接独特的自然环肽RA-V与近红外（NIR）荧光物质，然后将其加载到CPTP/RA-HALipo阳离子脂质体的核心中，而ALP可活化的磷酸二氢克托司汀（CPTP）被封装在HA壳中。在肿瘤微环境中，CPTP/RA-HALipo的HA壳将被血红酸酶部分降解，从而释放CPTP。被释放的磷酸二氢克托司汀可通过刷缘微细毛而活化磷酸酯的水解。剩余HA包裹的阳离子脂质体可以通过受体介导的内吞作用选择性进入过度表达CD44的细胞中的溶酶体，其中酸性微环境会降解脂质体以释放靶向线粒体的治疗和诊断双功能药物RA-S-S-Cy。更重要的是，Cy5.5的谷胱甘肽活化近红外荧光可实现体内和体外非侵入性的药物释放动态监测。这种特异性靶向细胞器和多刺激响应纳米颗粒对药物输送和释放显示出精确控制，从而导致优越的体外和/或体内抗癌效力。这种方法代表一种新型的交互式药物输送系统，可以协同作用以区分胞外、细胞膜和细胞内的靶点，以促进对药物释放的时空控制。

The design of advanced carriers that enable time- or stimulus-programmed drug release holds great promise to enhance the treatment efficacy in tumors. Here, hyaluronic acid (HA)-coated liposomes were designed to efficiently deliver multi-organelle-targeted and ALP/GSH dual-responsive prodrugs for combination therapy on colon tumors. In this system (designated CPTP/RA-HALipo), the unique natural cyclopeptide RA-V was linked covalently to a near-infrared (NIR) fluorophore through a disulfide linker, which was subsequently loaded in the cationic liposome core of CPTP/RA-HALipo, while the ALP-activatable phosphate CPT (CPTP) was encapsulated in the HA shell. In the tumor microenvironment, the HA shell of CPTP/RA-HALipo was partially degraded by HAase, thereby allowing the release of CPTP. The released phosphate prodrug CPTP was activated through hydrolysis of the phosphate esters by brush border-associated enzymes. The cationic liposome coated with the remaining HA could selectively enter CD44 overexpressed cells via receptor-mediated endocytosis into the lysosome, in which the acidic microenvironment degraded the liposomes to release the mitochondria-targeted theranostic agent RA-S-S-Cy. More significantly, the GSH-activatable NIR fluorescence of Cy5.5 made it possible to realize in vivo and in situ dynamic monitoring of drug release in a noninvasive manner. The organelle-specific and multi-stimuli responsive nanoparticles have shown precise control over drug delivery and release, leading to superior in vitro and/or in vivo anti-cancer efficacy. This approach represents a novel interactive drug delivery system that can synergistically differentiate the extracellular, cell membranal and intracellular targets to promote spatial and temporal control of drug release.