Engineered gold nanoparticles for accurate and full-scale tumor treatment via pH-dependent sequential charge-reversal and copper triggered photothermal-chemodynamic-immunotherapy

Abstract

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 Cu²⁺ 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 Cu²⁺ 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 Cu²⁺ ions were reduced to Cu⁺, which catalyzed the high concentration of intracellular H₂O₂ 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.