Inspired by natural saccharide-protein complexes, a stimuli-responsive biodegradable and branched glycopolymer–pyropheophorbide-a (Ppa) conjugate (BSP) with saccharide units for cancer therapy is constructed. A linear glycopolymeric conjugate (LSP), a branched glycopolymeric conjugate (BShP) from Ppa with long carbon chains, and a branched conjugate (BHSP) based on poly[N-(2-hydroxypropyl) methacrylamide] (polyHPMA) without saccharide units are prepared as controls. Through structure–activity relationship studies, BSP with a 3D network structure forms stable nanostructures via weak intermolecular interactions, regulating the stacking state of Ppa to improve the singlet oxygen quantum yield and the corresponding photodynamic therapy (PDT) effect. BSP shows high loading of olaparib, and are further coated with tumor cell membranes, resulting in a biomimetic nanomedicine (CM-BSPO). CM-BSPO shows highly efficient tumor targeting and cellular internalization properties. The engulfment of CM-BSPO accompanied with laser irradiation results in a prominent antitumor effect, evidenced by disruption of cell cycles in tumor cells, increased apoptosis and DNA damage, and subsequent inhibition of repair for damaged DNA. The mechanism for the synergistic effect from PDT and olaparib is unveiled at the genetic and protein level through transcriptome analysis. Overall, this biodegradable and branched glycopolymer–drug conjugate could be effectively optimized as a biomimetic nanomedicine for cancer therapy.

中文翻译：

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基于天然糖聚合物的仿生纳米药物利用肿瘤基因组不稳定性的协同治疗

受天然糖蛋白复合物的启发，构建了一种刺激响应性的可生物降解的支链糖聚合物-焦脱镁叶绿酸-a (Ppa) 缀合物 (BSP)，该缀合物具有用于癌症治疗的糖单元。一种线性糖聚合物偶联物 (LSP)、一种来自 Ppa 的具有长碳链的支链糖聚合物偶联物 (BShP)，以及一种基于 poly[ N ] 的支链偶联物 (BHSP)制备不含糖单元的-(2-羟丙基)甲基丙烯酰胺](聚HPMA)作为对照。通过构效关系研究，具有3D网络结构的BSP通过弱分子间相互作用形成稳定的纳米结构，调节Ppa的堆积状态，从而提高单线态氧量子产率和相应的光动力疗法（PDT）效果。BSP 显示出高负载的奥拉帕尼，并进一步被肿瘤细胞膜包裹，从而产生仿生纳米药物 (CM-BSPO)。CM-BSPO 显示出高效的肿瘤靶向和细胞内化特性。伴随激光照射的 CM-BSPO 的吞噬导致显着的抗肿瘤作用，这可以通过破坏肿瘤细胞中的细胞周期、增加细胞凋亡和 DNA 损伤以及随后抑制受损 DNA 的修复来证明。通过转录组分析，在遗传和蛋白质水平上揭示了 PDT 和奥拉帕尼的协同作用机制。总体而言，这种可生物降解的支链糖聚合物-药物偶联物可以有效地优化为用于癌症治疗的仿生纳米药物。