化学修饰CRISPR酶用于体内多器官基因组编辑
Chemically modified CRISPR enzymes for multi-organ genome editing in vivo
bioRxiv · 2026 年 9 月 16 日 · Christopher M Baehr, Alzbeta Ressnerova, Min Kang 等 23 人
递送是体内基因组编辑疗法的主要障碍，CRISPR核糖核蛋白编辑活性高但无法自主进入细胞和靶向组织。研究者开发了PERCEPT递送平台，对CRISPR酶进行可逆共价修饰，模块化安装屏蔽聚合物、两亲性递送肽和靶向配体，并在胞质内无痕释放天然编辑器。含神经元靶向配体TET1的配方在局部纹状体给药后编辑了约56%的纹状体体积和编辑区域内78%的神经元；在亨廷顿病R6/2模型中编辑突变HTT转基因，减少突变亨廷顿蛋白聚集并改善炎症相关转录程序。其他组织适配配方分别实现53% Müller胶质细胞编辑、肌肉荧光增强十倍、鼻腔给药后肺气道上皮细胞编辑持续三个月。这确立了可逆化学修饰作为跨组织CRISPR递送的通用策略，尚未经同行评审。
为什么推荐给您：可逆化学修饰实现多器官CRISPR递送的新平台，体内编辑效率高，转化前景强。
不需要生物学背景，多打比方
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摘要Abstract
Delivery remains the main obstacle to the development of in vivo genome editing therapies. CRISPR ribonucleoproteins confer high editing activity with transient exposure but lack intrinsic cell entry and targeting. Here we introduce PERCEPT, a delivery platform featuring reversible, covalent modification of CRISPR enzymes. PERCEPT enables modular installation of shielding polymers, amphiphilic delivery peptides and targeting ligands, allowing traceless cytosolic release of the native editor. A formulation incorporating an amphiphilic delivery peptide and the neuron-targeting ligand TET1 edited approximately 56% of striatal volume and 78% of neurons within edited regions after local striatal administration. In the R6/2 Huntington's disease model, PERCEPT mediated targeted editing of the mutant human HTT transgene, reducing mutant huntingtin aggregate burden and shifting local transcriptional programs away from inflammatory and injury-associated states. Tissue-adapted formulations edited 53% of Müller glia following intravitreal delivery, increased skeletal muscle reporter fluorescence tenfold versus unconjugated control following intramuscular injection, and enabled lung airway epithelial cell that persisted for three months following intranasal delivery. Rapid screening revealed that local anatomical and cellular barriers require distinct surface display for optimal editing. These results establish reversible chemical modification as a general strategy for adapting CRISPR enzyme delivery across multiple target tissues in vivo .