Highly efficient tumor-targeted therapy remains a great challenge due to the complexity and heterogeneity of tumor tissues. Herein, we developed an in vivo two-step tumor-targeting strategy by combining metabolic lipid-engineering with a stain-promoted azide–alkyne 1,3-dipolar cycloaddition (SPAAC) reaction, independent of the tumor microenvironment and cell phenotype. Firstly, exogenously-supplied azidoethyl-cholines (AECho) were metabolically incorporated into the cell membranes in tumor tissues through the intrinsic biosynthesis of phosphatidylcholine. The pre-inserted and accumulated azido groups (N₃) could subsequently serve as ‘artificial chemical receptors’ for the specific anchoring of dibenzocyclooctyne (DBCO) modified biomimetic nanoparticles (DBCO-RBCG@ICG) via in situ click chemistry, resulting in significantly enhanced tumor-targeting and then an improved photothermal therapy effect. Such a two-step targeting strategy based on these cutting-edge techniques provided new insights into the universal and precise functionalization of living tissues for site-specific drug delivery in the diagnosis and treatment of various diseases.

中文翻译：

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通过代谢脂质工程与原位点击化学相结合的两步靶向肿瘤治疗

由于肿瘤组织的复杂性和异质性，高效的肿瘤靶向治疗仍然是一个巨大的挑战。在本文中，我们通过结合代谢脂质工程与污点促进的叠氮化物-炔烃1,3-偶极环加成（SPAAC）反应相结合，开发了一种体内两步肿瘤靶向策略，与肿瘤微环境和细胞表型无关。首先，通过磷脂酰胆碱的内在生物合成，将外源提供的叠氮乙基胆碱（AECho）代谢整合到肿瘤组织的细胞膜中。预先插入和积累的叠氮基团（N ₃）随后可以用作“人工化学受体”，用于特定地锚定二苯并环辛炔（DBCO）修饰的仿生纳米颗粒（DBCO-RBCG @ ICG）通过原位点击化学，可以显着增强肿瘤靶向性，进而改善光热疗法的效果。基于这些尖端技术的这种两步式靶向策略为活体组织的通用和精确功能化提供了新的见解，从而可以在各种疾病的诊断和治疗中进行特定部位的药物递送。