Mass-Ratio-Controlled Organ-Selective Phosphatidyl Polymer Carrier for In Vivo Targeted mRNA Delivery.

IF 16 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

ACS Nano Pub Date : 2025-10-01 DOI:10.1021/acsnano.5c12386

Hanqin Zhao,Yuxi Gao,Yibo Qi,An Ziyue,Minhui Li,Jie Chen,Sheng Ma,Wantong Song,Xuesi Chen

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引用次数: 0

Abstract

Organ-selective mRNA transfection enables precise regulation of gene expression in specific tissues and represents a pivotal strategy for advancing mRNA therapeutics toward multiorgan and multi-indication applications. However, prevailing delivery systems rely on tissue-specific ligands or polyplex chemical modifications, limiting the modularity, scalability, and clinical translatability of delivery systems. Herein, we report a mass-ratio-controlled organ-selective (MACO) mRNA delivery platform based on phosphatidyl polyethylenimine derivatives (PEI-PPs). Impressively, the MACO platform enables precise and reversible switching of mRNA transfection among the spleen (94%), liver (78%), and lung (95%) by simply adjusting the mass ratio of PEI-PP to mRNA, without requiring additional targeting ligands, charge modifiers, or chemical modifications. Mechanistic investigations revealed that varying mass ratios generate polyplexes with distinct surface charge and pKa profiles, which in turn adsorb plasma protein coronas forming specific "protein fingerprints" that mediate organ-selective capability. The MACO mechanism represents the demonstration of organ-selective mRNA delivery governed solely by formulation parameters rather than polyplex structural alterations, providing a universal strategy to finely tune the mRNA multiorgan target.

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用于体内靶向mRNA递送的质量比控制器官选择性磷脂酰聚合物载体。

器官选择性mRNA转染能够精确调节特定组织中的基因表达，是推进mRNA治疗向多器官和多适应症应用的关键策略。然而，目前的递送系统依赖于组织特异性配体或多组分化学修饰，限制了递送系统的模块化、可扩展性和临床可翻译性。在此，我们报道了一个基于磷脂酰聚乙烯亚胺衍生物（PEI-PPs）的质量比例控制的器官选择性（MACO） mRNA传递平台。令人印象深刻的是，MACO平台通过简单地调整PEI-PP与mRNA的质量比，无需额外的靶向配体、电荷修饰剂或化学修饰，即可实现脾脏（94%）、肝脏（78%）和肺（95%）之间mRNA转染的精确和可逆切换。机制研究表明，不同的质量比会产生具有不同表面电荷和pKa谱的多聚物，这些多聚物反过来吸附血浆蛋白冠状体，形成特异性的“蛋白质指纹”，介导器官选择能力。MACO机制表明，mRNA的器官选择性传递仅受配方参数的控制，而不受复合结构改变的影响，这为精细调节mRNA的多器官靶点提供了一种通用策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Nano 工程技术-材料科学：综合

CiteScore

26.00

自引率

4.10%

发文量

1627

审稿时长

1.7 months

期刊介绍： ACS Nano, published monthly, serves as an international forum for comprehensive articles on nanoscience and nanotechnology research at the intersections of chemistry, biology, materials science, physics, and engineering. The journal fosters communication among scientists in these communities, facilitating collaboration, new research opportunities, and advancements through discoveries. ACS Nano covers synthesis, assembly, characterization, theory, and simulation of nanostructures, nanobiotechnology, nanofabrication, methods and tools for nanoscience and nanotechnology, and self- and directed-assembly. Alongside original research articles, it offers thorough reviews, perspectives on cutting-edge research, and discussions envisioning the future of nanoscience and nanotechnology.