由于低氧肿瘤微环境（TME）不仅会限制治疗效果，还会导致肿瘤复发和转移，而血管栓塞引起的肿瘤细胞内加剧的低氧水平是肿瘤治疗的主要挑战之一。低氧诱导型前药（HAPs）的化疗效果可以通过加剧缺氧来增强，肿瘤栓塞和基于HAP的化疗的组合表现为癌症治疗的一种有前途的策略。在此，我们采用简单的一锅法将光敏剂氯林e6（Ce6），凝血酶（Thr）和AQ4N装载到磷酸钙纳米载体中，构建了一种多途径受酸响应的纳米平台（TACC NP），以获得更好的低氧诱导化疗效果。在酸性TME中，TACC NP能够被降解以释放Thr和Ce6，从而在激光照射下破坏肿瘤血管并消耗肿瘤内的氧气。因此，肿瘤细胞内的低氧水平能够被显著加剧，从而进一步增强AQ4N的化疗效果。在体内荧光成像的指导下，TACC NP表现出了优异的肿瘤栓塞/光动力学/前药协同治疗效果，具有良好的生物安全性。版权所有©2023 Elsevier Ltd.

Since the hypoxia tumor microenvironment (TME) will not only limit the treatment effect but also cause tumor recurrence and metastasis, intratumoral aggravated hypoxia level induced by vascular embolization is one of the major challenges in tumor therapy. The chemotherapeutic effect of hypoxia-activated prodrugs (HAPs) could be enhanced by the intensified hypoxia, the combination of tumor embolization and HAP-based chemotherapy exhibits a promising strategy for cancer therapy. Herein, an acidity-responsive nanoplatform (TACC NP) with multiple pathways to benefit the hypoxia-activated chemotherapy is constructed by loading the photosensitizer Chlorin e6 (Ce6), thrombin (Thr), and AQ4N within the calcium phosphate nanocarrier via a simple one-pot method. In the acidic TME, TACC NPs could be degraded to release Thr and Ce6, resulting in the destruction of tumor vessels and consumption of intratumoral oxygen under laser irradiation. Therefore, the intratumoral hypoxia level could be significantly aggravated, further leading to the enhanced chemotherapeutic effect of AQ4N. With the guidance of in vivo fluorescence imaging, the TACC NPs exhibited excellent tumor embolization/photodynamic/prodrug synergistic therapeutic effects with good biosafety.Copyright © 2023 Elsevier Ltd. All rights reserved.