Free radical therapy based on 5-aminolevulinic acid (ALA, a precursor of the photosensitizer protoporphyrin IX (PpIX)) has been approved by the US Food and Drug Administration for clinical tumor treatment. However, PpIX can be quickly converted into photoinactive heme, leading to unexpectedly paused production of free radicals and severely hindering its therapeutic benefits. Here, inspired by the natural biotransformation of ALA (ALA-PpIX-heme), an uninterrupted reactive oxygen species generator (URG) that converts useless heme to peroxidase mimics via intracellular self-assembly is developed. The URG is prepared by enwrapping ALA-loaded polyamide-amine dendrimers in red blood cell membrane vesicles with a further surface modification of G-quadruplex-structured AS1411. The URGs realize “¹O₂−•OH” uninterrupted generation through “recycling waste” in two steps: i) PpIX generates ¹O₂ under laser irradiation; and ii) the photoinactive metabolite heme self-assembled with AS1411 to catalyze H₂O₂ conversion into •OH. Interestingly, the specific generation of ¹O₂ in mitochondria and •OH in nuclei further augments the free-radical-induced damage. It is demonstrated that URG can continuously produce free radicals for 6 h postirradiation, and shows 3.3-times more than that of the nonassembly group, achieving nearly 80% regression of tumors in vivo.

中文翻译：

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一种细胞内自组装驱动的不间断 ROS 发生器增强基于 5-氨基乙酰丙酸的肿瘤治疗

基于 5-氨基乙酰丙酸（ALA，光敏剂原卟啉 IX (PpIX) 的前体）的自由基疗法已被美国食品和药物管理局批准用于临床肿瘤治疗。然而，PpIX 可以迅速转化为光非活性血红素，导致自由基的产生意外暂停并严重阻碍其治疗效果。在这里，受 ALA (ALA-PpIX-heme) 的自然生物转化的启发，开发了一种不间断的活性氧生成器 (URG)，它通过细胞内自组装将无用的血红素转化为过氧化物酶模拟物。URG 是通过将负载 ALA 的聚酰胺-胺树枝状大分子包裹在红细胞膜囊泡中来制备的，并对 G-四链体结构的 AS1411 进行进一步的表面修饰。URG 实现“ ¹ O ₂−•OH”通过两步“回收废物”不间断产生： i) PpIX在激光照射下产生¹ O _{2 ；}ii)与AS1411自组装的光非活性代谢物血红素催化H ₂ O ₂转化为•OH。有趣的是，线粒体中¹ O ₂和细胞核中 •OH 的特异性生成进一步增强了自由基诱导的损伤。经证实，URG照射后6 h可连续产生自由基，是非组装组的3.3倍，体内肿瘤消退率接近80%。