Blocked bioorthogonal chemistry enabled switchable bioorthosome to improve liposomal drug delivery for glioblastoma therapy  

作　　者：Chao Wang Jie Wu Zhiran Duan Yuqing Pan Haijing Qu Wei Cheng Ning Wang Han Chen Xiaoli Gao Mengqing Hou Ying Zhang Xiangdong Xue 

机构地区：[1]Key Laboratory of Resource Biology and Biotechnology of Western China,Ministry of Education,Provincial Key Laboratory of Biotechnology,College of Life Sciences,Northwest University,Xi'an 710069,China [2]Shanghai Frontiers Science Center of Drug Target Identification and Delivery,School of Pharmaceutical Sciences,National Key Laboratory of Innovative Immunotherapy,Shanghai Jiao Tong University,Shanghai 200240,China

出　　处：《Nano Research》2025年第4期388-401,共14页纳米研究(英文版)

基　　金：the National Natural Science Foundation of China(Nos.82172084,81803002,and 32371342);STI2030-Major Projects(No.2022ZD0212500);Shanghai Frontiers Science Center of Drug Target Identification and Delivery(No.ZXWH2170101);Shaanxi Provincial Education Department serves local industrialization projects(No.20JC035);Xi'an Science and Technology Bureau of Shaanxi province-scientific and technological personnel service enterprise project(No.22GXFW0133);Shaanxi innovation team project(No.2023-CXTD-58).

摘　　要：Glioblastoma(GBM)interventions necessitate exceptional precision due to the presence of blood-brain barrier(BBB)and its intricate co-growth with neuron and glial cells.Here,we developed a blocked bioorthogonal chemistry enabled liposome,termed Bioorthosome,with switchable BBB-crossing ligand that could block the bioorthogonal moieties in normal tissue and blood circulation.Upon traversing the BBB and reaching tumor region,the BBB-crossing ligand could detach from the Bioorthosome under acidic tumor microenvironment and switch to the bioorthogonal moieties to react with the metabolically expressed azide-containing sialylations on GBM cell surface.This switchable bioorthogonal chemistry ensures that only GBM cells are targeted,thereby enhancing the precision of liposomal drug delivery.In vitro and in vivo studies have demonstrated that the Bioorthosome efficiently crosses the BBB and undergoes a ligand-switching process to selectively recognize GBM cells while sparing normal brain tissue,leading to enhanced therapeutic efficacy and reduced off-target accumulation.By integrating bioorthogonal reactions with a tumor microenvironment-responsive ligand-switching mechanism,our Bioorthosome design overcomes the limitations of inefficient BBB permeability and suboptimal anti-GBM drug delivery,paving the way for more precise GBM-targeted therapies and the advancement of more effective treatment strategies.

关 键 词：GLIOBLASTOMA bioorthogonal chemistry blood-brain barrier LIPOSOME TUMOR-TARGETING 

分 类 号：R943[医药卫生—药剂学]