尽管医学技术显著进步，癌症仍是高死亡率和治疗选择有限的疾病。预计到2030年，每年约有3000万人因癌症死亡。化疗是治疗癌症的主要方法，但其效果受药物耐药性和对正常细胞毒性的限制。传统化疗药物在区分正常细胞和肿瘤细胞方面表现不佳，导致正常组织受损，如骨髓和胃肠道等。肿瘤微环境（TME）具有酸性pH值和缺氧等特征，缺氧既是治疗抵抗的因素，也是靶向治疗的契机。肿瘤微环境激活型前药已成为精准医学中的一种有前景的策略。然而，肿瘤微环境中的内源性刺激通常不足且分布不均，阻碍了前药的有效和快速转化，需要结合补充性治疗策略以增强治疗效果。

本研究提出了一种自身协同治疗方法，将乏氧激活紫杉醇前药（pro-PTX）与近红外二区（NIR-II）光触发的光热疗法（PTT）相结合，以增强肿瘤治疗效果。首先，通过引入电子吸引的三氟甲基取代基合成了具有强大NIR-II光捕获能力、高效的光-热转化和优异的光稳定性的有机聚合物。高性能NIR-II光热聚合物随后用作包封乏氧响应性pro-PTX前药的基质，形成纳米核心，进一步用来包裹源自自然杀伤细胞（NK）的细胞膜。仿生纳米平台相对于正常细胞对肿瘤细胞表现出了更强的亲和性，这归因于NK细胞膜蛋白的天然肿瘤识别能力。暴露于NIR-II激光下，光热剂诱导局部高温，不仅有助于直接清除肿瘤，还加重了肿瘤微环境中的乏氧。这进一步加速了乏氧响应型前药的释放。因此，NIR-II PTT和化疗的协同效应有效诱导了癌细胞凋亡并抑制了肿瘤生长。所开发的纳米平台，整合了乏氧响应型前药、高性能NIR-II PTT剂介导的补充光疗以及NK细胞启发的活性靶向，代表了一种精准且增强的肿瘤治疗策略。

Despite significant advances in medical technology, cancer remains a disease with high mortality and limited treatment options. It is estimated that by 2030, approximately 30 million people will die annually from cancer. Chemotherapy is the cornerstone of cancer treatment, but its efficacy is hindered by drug resistance and severe toxicity to normal cells. Traditional chemotherapeutic agents are often poor at distinguishing between normal and tumor cells, leading to damage to healthy tissues such as bone marrow and the gastrointestinal tract. The tumor microenvironment (TME) is characterized by acidic pH and hypoxia, which are both factors in treatment resistance and opportunities for targeted therapy. Tumor microenvironment-activated prodrugs have emerged as a promising strategy in precision medicine. However, the endogenous stimuli in the tumor microenvironment are often insufficient and unevenly distributed, impeding efficient and rapid prodrug conversion, necessitating the incorporation of complementary therapeutic strategies to amply treatment effectiveness.

This study presents a self-synergistic therapeutic approach that combines hypoxia-activated paclitaxel prodrug (pro-PTX) with near-infrared-II (NIR-II) light-triggered photothermal therapy (PTT) for boosted tumor treatment. Initially, an organic polymer with strong NIR-II light harvesting capability, efficient photo-to-heat conversion, and excellent photostability was meticulously synthesized by introducing electron-withdrawing trifluoromethyl substituent. The high-performance NIR-II photothermal polymer then served as the matrix to encapsulate the hypoxia-responsive pro-PTX prodrug, forming the nanocore, on which the cell membrane derived from natural killer (NK) cells was further cloaked. The biomimetic nanopaltform exhibited a superior affinity towards tumor cells compared to normal cells, owing to the inherent tumor-recognition capability of NK cell membrane proteins. Upon exposure to NIR-II laser, the photothermal agent induced localized hyperthermia, facilitating not only direct tumor eradication but also exacerbating hypoxia within the tumor microenvironment. This, in turn, expedited the release of hypoxia-responsive prodrugs. Consequently, the synergistic effect of NIR-II PTT and chemotherapy efficiently induced cancer cell apoptosis and inhibited tumor growth. The developed nanoplatform, integrating hypoxia-responsive prodrug, high-performance NIR-II PTT agent-mediated complementary phototherapy, and NK cell-inspired active targeting, represents a promising strategy for precise and boosted tumor treatment.