纳米医学已革新了癌症治疗的格局。聚吡咯（PPy）是一种常见的杂环共轭型导电高分子有机聚合物，PPy纳米结构具有粒径大小可控性、良好的生物相容性、强吸光度和在近红外I/II区域的高光热转换效率的显著优点，是优异的光热转换剂（PTAs），可用于肿瘤的光热治疗。然而，目前PPy光热纳米制剂的应用依旧面临着巨大的挑战。
首先，肿瘤自防御系统会促进肿瘤细胞的损伤修复、抗凋亡和免疫逃逸等。例如，热休克蛋白（HSPs）在高温环境下能够修复细胞热损伤，有效阻止肿瘤细胞的坏死凋亡，增强肿瘤对高温的耐受性，从而削弱现有光热疗法的治疗效果。此外，纳米材料在体内代谢过程尚不明晰，关于其潜在安全性的问题仍待解答。这些挑战的存在，无疑为光热纳米制剂在癌症治疗领域的应用带来了更大的难度和不确定性。因此，开发一种能够抑制肿瘤热抵抗功能且能在发挥作用后自降解的纳米体系是解决上述问题的重要策略。
基于此，本研究设计并开发了一种葡萄糖氧化酶（GOx）修饰的铼纳米团簇掺杂的聚吡咯纳米粒（Re@ReP-G），“一石二鸟”地实现了酶介导肿瘤凋亡放大和酶促代谢清除。Re@ReP-G通过GOx诱导的酶促氧化反应减少了三磷酸腺苷（ATP）的产生，进而导致HSP70、HSP90和抗凋亡蛋白Bcl-2的下调，以及促凋亡蛋白Bax的表达和细胞色素c（Cyt-c）的释放。激光诱导的高热效应进一步促进了这些过程，最终导致严重的肿瘤细胞凋亡。与此同时，酶促反应副产物H₂O₂可催化Re@ReP-G纳米结构中的铼纳米团簇单质从外向内发生铼酸化，从而加速其体内代谢清除。这种基于Re@ReP-G的“一石二鸟”疗法为实现更有效的肿瘤凋亡和安全的代谢机制提供了有效工具。

Nanomedicine has revolutionized the landscape of cancer therapy. Polypyrrole (PPy), a common heterocyclic conjugated conductive polymer, possesses remarkable advantages such as controllable particle size, excellent biocompatibility, strong absorbance, and high photothermal conversion efficiency in the near-infrared I/II region, making it an outstanding photothermal conversion agent (PTA) for tumor photothermal therapy. However, current PPy-based photothermal nanoagents also face significant challenges.
Firstly, the tumor's self-defense system can promote damage repair, anti-apoptosis, and immune escape in tumor cells. For instance, heat shock proteins (HSPs) can repair cellular thermal damage under high-temperature conditions, effectively preventing necrosis and apoptosis in tumor cells, enhancing tumor tolerance to hyperthermia, and thus weakening the therapeutic effect of existing photothermal therapies. Additionally, the uncertain fate of nanomaterials during the in vivo metabolism raises concerns regarding their safety. These challenges introduce complexity and ambiguity to the application of photothermal nanoagents in cancer therapy. Therefore, there is a pressing need to develop nanosystems capable of inhibiting tumor thermal resistance and self-degrading after fulfilling their therapeutic effects.
In this project, we developed glucose oxidase (GOx)-modified rhenium nanocluster-doped polypyrrole nanoparticles (Re@ReP-G) to achieve both enzyme-mediated tumor apoptosis amplification and enzymatic metabolic clearance in a "one-stone-two-birds" nanosystem. On the one hand, Re@ReP-G can reduce the production of adenosine triphosphate (ATP) through GOx-induced enzymatic oxidation, leading to downregulation of HSP70, HSP90, and anti-apoptotic protein Bcl-2, along with the expression of apoptotic protein Bax and the release of cytochrome c (Cyt-c). The application of laser can further induce hyperthermia effect, resulting in severe tumor cell apoptosis. On the other hand, the enzymatic byproduct H₂O₂ can catalyze the outward-to-inward rhenation of rhenium nanoclusters in the Re@ReP-G nanostructure, thereby accelerating its metabolic clearance in vivo. This innovative therapeutic approach based on Re@ReP-G not only provides an efficient way to enhance tumor apoptosis, but also establishes a metabolic pathway for clearance, marking it a promising nanomedication for cancer treatment.