Abstract：
Radiotherapy is a mainstream modality for breast cancer treatment that employs ionizing radiation (IR) to damage tumor cell DNA and elevate ROS stress, which demonstrates multiple clinically-favorable advantages including localized treatment and low invasiveness. However, breast cancer cells may activate the p53-mediated cell cycle regulation in response to radiotherapy to repair IR-induced cellular damage and facilitate post-treatment survival. F-Box and WD Repeat Domain Containing 7 (FBXW7) is a promoter of p53 degradation and critical nexus of cell proliferation and survival events. Herein, we engineered a cooperative radio-ferroptosis-stimulatory nanomedicine through coordination-driven self-assembly between ferroptosis-inducing Fe2+ ions and FBXW7-inhibiting DNAzymes and further modification of tumor-targeting dopamine-modified hyaluronic acid (HA). The nanoassembly could be selectively internalized by breast cancer cells and disintegrated in lysosomes to release the therapeutic payload. DNAzyme readily abolishes FBXW7 expression and stabilizes phosphorylated p53 to cause irreversible G2 phase arrest for amplifying post-IR tumor cell apoptosis. Meanwhile, the p53 stabilization also inhibits the SLC7A11-cystine-GSH axis, which combines with the IR-upregulated ROS levels to amplify Fe2+-mediated ferroptotic damage. The DNAzyme-Fe-HA nanoassembly could thus systematically boost the tumor cell damaging effects of IR, presenting a simple and effective approach to augment the response of breast cancer to radiotherapy. STATEMENT OF SIGNIFICANCE: To overcome the intrinsic radioresistance in breast cancer, we prepared co-assembly of Fe2+ and FBXW7-targeted DNAzymes and modified surface with dopamine conjugated hyaluronic acid (HA), which enabled tumor-specific FBXW7-targeted gene therapy and ferroptosis therapy in IR-treated breast cancers. The nanoassembly could be activated in acidic condition to release the therapeutic contents. Specifically, the DNAzymes could selectively degrade FBXW7 mRNA in breast cancer cells to simultaneously induce accumulation of p53 and retardation of NHEJ repair, eventually inducing irreversible cell cycle arrest to promote apoptosis. The p53 stabilization would also inhibit the SLC7A11/GSH/GPX4 axis to enhance Fe2+ mediated ferroptosis. These merits could act in a cooperative manner to induce pronounced tumor inhibitory effect, offering new approaches for tumor radiosensitization in the clinics.
摘要：
放射治疗是乳腺癌治疗的主流模式，它采用电离辐射（IR）来损伤肿瘤细胞DNA并提高ROS应激。这证明了多个临床上有利的优势，包括局部治疗和低侵袭性。然而,乳腺癌细胞可能激活p53介导的细胞周期调控,以响应放疗,修复IR诱导的细胞损伤并促进治疗后存活.F-Box和WD重复结构域包含7（FBXW7）是p53降解的启动子，也是细胞增殖和存活事件的关键联系。在这里，我们通过诱导铁凋亡的Fe2+离子和FBXW7抑制DNA酶之间的协调驱动自组装,并进一步修饰靶向肿瘤的多巴胺修饰的透明质酸(HA),设计了一种合作的放射铁凋亡刺激纳米药物.纳米组装体可以被乳腺癌细胞选择性内化并在溶酶体中崩解以释放治疗有效负载。DNAzyme容易消除FBXW7表达并稳定磷酸化的p53，以引起不可逆的G2期停滞，从而放大IR后肿瘤细胞凋亡。同时,p53稳定还抑制SLC7A11-胱氨酸-GSH轴，与IR上调的ROS水平结合以放大Fe2介导的铁细胞损伤。因此，DNAzyme-Fe-HA纳米组装体可以系统地增强IR的肿瘤细胞损伤作用，提出了一种简单有效的方法来增强乳腺癌对放射治疗的反应。重要声明：为了克服乳腺癌的内在放射抗性，我们制备了Fe2+和FBXW7靶向的DNA酶的共组装体，并与多巴胺缀合的透明质酸（HA）修饰了表面，在IR治疗的乳腺癌中实现了肿瘤特异性FBXW7靶向基因治疗和铁凋亡治疗。纳米组装体可在酸性条件下活化以释放治疗内容物。具体来说,DNA酶可以选择性降解乳腺癌细胞中的FBXW7mRNA，同时诱导p53的积累和NHEJ修复的延迟，最终诱导不可逆的细胞周期阻滞以促进细胞凋亡。p53稳定化还将抑制SLC7A11/GSH/GPX4轴以增强Fe2+介导的铁凋亡。这些优点可以以合作的方式产生明显的肿瘤抑制作用，为临床上的肿瘤放射增敏提供了新的方法。
