National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, 210093, China.
Department of Pediatric Stomatology, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China.
Biomaterials. 2021 Dec;279:121224. doi: 10.1016/j.biomaterials.2021.121224. Epub 2021 Oct 22.
Cell-based drug delivery system holds a great promise in anticancer treatment, due to its potential of maximizing therapeutic efficacy while minimizing adverse effects. However, current cell system can only deliver drugs in tumor lesions, but lack an ability to target subcellular locus of therapeutic actions, thereby compromising anticancer efficacy. Herein, we bioengineered living neutrophils as a novel type of "Photoactive neutrophil" (PAN) with capabilities of self-amplified multistage targeting and inflammation response for enhancing mitochondria-specific photo-chemotherapy. PAN encapsulated multifunctional nanocomplex (RA/Ce6) of RGD-apoptotic peptide conjugate (RA) decorated liposomal photosensitizer Ce6, and could overcome tumor barriers to selectively release RA/Ce6 within tumor. Consequently, RA/Ce6 actively entered cancer cells and accumulated in mitochondria to trigger combined photodynamic therapy (PDT) and RA-induced mitochondrial membrane disruption, resulting in enhanced therapeutic effects. Importantly, PAN exhibited inflammation amplified tumor targeting after PDT, and initiated combined photo-chemotherapy to suppress tumor growth without adverse effects, leading to prolonged mice survival. Therefore, PAN represents the first multistage targeted cell therapy, and brings new insights into cancer treatment.
基于细胞的药物输送系统在癌症治疗中具有很大的应用前景，因为它有可能在最大限度地提高治疗效果的同时，最大限度地减少不良反应。然而，目前的细胞系统只能在肿瘤病变部位输送药物，但是缺乏靶向治疗作用的亚细胞位置的能力，从而影响了抗癌效果。在此，我们将活的嗜中性粒细胞生物工程化为一种新型的“光活性嗜中性粒细胞”(PAN)，具有自我放大的多阶段靶向和炎症反应能力，可增强线粒体特异性光化学疗法。PAN 封装了多功能纳米复合物（RA/Ce6），其中包含 RGD-凋亡肽缀合物（RA）修饰的脂质体光敏剂 Ce6，能够克服肿瘤屏障，在肿瘤内选择性释放 RA/Ce6。因此，RA/Ce6 主动进入癌细胞并在其中积累在线粒体中，以引发联合光动力疗法（PDT）和 RA 诱导的线粒体膜破裂，从而增强治疗效果。重要的是，PAN 在 PDT 后表现出炎症放大的肿瘤靶向作用，并启动联合光化学疗法以抑制肿瘤生长而无不良反应，从而延长了小鼠的存活时间。因此，PAN 代表了第一种多阶段靶向细胞疗法，为癌症治疗带来了新的见解。
