Liu Jie, Tang Wenjuan, Chen Li, Zhang Qianqian, Liu Tao, Qin Longyu, Zhang Yanmin, Chen Xin
Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
Biomaterials. 2025 Oct;321:123322. doi: 10.1016/j.biomaterials.2025.123322. Epub 2025 Apr 3.
Current anti-tumor strategies majorly rely on the targeted delivery of functional nanomedicines to tumor region, neglecting the importance of effective infiltration of these nanomedicines in whole tumor tissue. This process normally causes the quick endocytosis by the tumor cells at surface layer of tumor tissue, resulting in the restriction of the penetration of these nanomedicines and limited therapeutic region, which would not be able to treat the entire tumor tissue. Herein, we prepared a series of engineered gold nanoparticles (Au-MBP NPs) with step-wise charge reversal in different acid environments that could entirely infiltrate into the whole tumor tissue and then perform tumor-specific photothermal-chemodynamic-immunotherapy to achieve the complete and accurate tumor treatment. These Au-MBP NPs consisted of AuNPs, thiol modified piperidine (SH-PD, charge reversal group), thiol modified benzoyl thiourea (SH-BTU, copper chelator) and 11-mercaptoundecanoic acid (MUA) with different proportions. Once these Au-MBP NPs arrived tumor tissue, the decreasing pH values from shallow to deep region of tumor tissue separately induced the charge reversal of these nanoparticles from negative to positive, allowing them to bind with negatively charged tumor cells at designed area to occupy the whole tumor for further therapy. Following with the internalization by tumor cells, these Au-MBP NPs would selectively capture the excessive Cu to decrease the available copper in tumor cells, resulting in the inhibition of tumor metastasis via the copper metabolism blockade. On one hand, the captured Cu also induced the aggregation of Au-MBP NPs, which in situ generated the photothermal agents in tumor cells for tumor-specific photothermal therapy (PTT). On the other hand, the chelated Cu ions were reduced to Cu, which catalyzed the high concentration of intracellular HO to produce cytotoxic hydroxyl radical (•OH), exerting tumor-specific chemodynamic therapy (CDT). Furthermore, the immune-associated tumor antigens were also generated during PTT and CDT processes via immunogenic cell death (ICD), which further matured the dendritic cells (DCs) and then activated CD4 and CD8 T cells to turn on the immunotherapy, resulting in additional anti-tumor and anti-metastasis effects. Both in vitro and in vivo results indicated that these Au-MBP NPs possessed enormous potential for effectively suppressing primary and metastatic tumors.
当前的抗肿瘤策略主要依赖于将功能性纳米药物靶向递送至肿瘤区域，而忽视了这些纳米药物在整个肿瘤组织中有效渗透的重要性。这一过程通常会导致肿瘤组织表层的肿瘤细胞快速内吞，从而限制了这些纳米药物的渗透以及治疗区域，无法对整个肿瘤组织进行治疗。在此，我们制备了一系列在不同酸性环境中具有逐步电荷反转特性的工程化金纳米粒子（Au-MBP NPs），其能够完全渗透到整个肿瘤组织中，然后进行肿瘤特异性光热-化学动力学-免疫治疗，以实现完整且精准的肿瘤治疗。这些Au-MBP NPs由不同比例的金纳米粒子（AuNPs）、硫醇修饰的哌啶（SH-PD，电荷反转基团）、硫醇修饰的苯甲酰硫脲（SH-BTU，铜螯合剂）和11-巯基十一烷酸（MUA）组成。一旦这些Au-MBP NPs到达肿瘤组织，肿瘤组织从浅到深区域pH值的降低会分别诱导这些纳米粒子的电荷从负向正反转，使其能够在特定区域与带负电荷的肿瘤细胞结合，占据整个肿瘤以进行进一步治疗。随着被肿瘤细胞内化，这些Au-MBP NPs会选择性地捕获过量的铜，从而降低肿瘤细胞中可利用的铜，通过铜代谢阻断抑制肿瘤转移。一方面，捕获的铜还会诱导Au-MBP NPs聚集，在肿瘤细胞中原位产生光热剂用于肿瘤特异性光热治疗（PTT）。另一方面，螯合的铜离子被还原为铜，催化细胞内高浓度的过氧化氢产生细胞毒性羟基自由基（•OH），发挥肿瘤特异性化学动力学治疗（CDT）。此外，在PTT和CDT过程中还会通过免疫原性细胞死亡（ICD）产生免疫相关肿瘤抗原，进一步使树突状细胞（DCs）成熟，然后激活CD4和CD8 T细胞开启免疫治疗，产生额外的抗肿瘤和抗转移作用。体外和体内实验结果均表明，这些Au-MBP NPs在有效抑制原发性和转移性肿瘤方面具有巨大潜力。
