2024.08.31《Probing the interaction mechanisms of lipid nanoparticle-encapsulated mRNA with surfaces of diverse functional groups: Implication for mRNA transport》

在《Chemical Engineering Science》最新发表的研究中，利用原子力显微镜（AFM）力谱技术，系统阐明了mRNA脂质纳米颗粒与不同官能团表面的相互作用机制，首次明确羟基是介导其表面附着的关键位点，为理性设计递送系统及功能表面提供了直接理论指导。mRNA疗法依赖于LNP载体，但其与生物或工程表面的附着效率受微观作用力调控，机制不明。本研究将方法学与机理阐释进行深度结合：将AFM探针分别修饰-COOH、-OH、-NH2、-PO3H2及-CH3等基团，在生理环境下直接定量测量并分析其与mRNA-LNP的界面力。研究表明，氢键与静电相互作用的竞争协同决定粘附行为，-OH与带负电的mRNA-LNP存在静电排斥，但其优异的氢键形成能力使其净吸引力最大，因而成为最有利的结合位点。该研究主要贡献体现在三方面：在理论上，系统揭示了官能团通过调控氢键与静电作用影响mRNA-LNP界面行为的物理化学机制，深化了对核酸纳米载体传输过程的理解；在方法上，建立了利用功能化AFM探针研究复杂纳米生物颗粒界面相互作用的有效方式；在应用上，明确指出富含-OH的表面（如细胞膜糖层）更易结合mRNA-LNP，从而为优化靶向递送、设计防污染医疗器械或高效分离膜材料提供了明确的分子设计依据，对推动mRNA药物及相关生物技术发展具有重要价值。

该文的第一作者为：王静懿，通讯作者为：曾宏波教授。

In a recent study published in Chemical Engineering Science, atomic force microscopy (AFM) force spectroscopy was employed to systematically elucidate the interaction mechanisms between mRNA lipid nanoparticles (LNPs) and surfaces functionalized with different groups. For the first time, hydroxyl (-OH) groups were identified as key sites mediating the surface adhesion of mRNA-LNPs, providing direct theoretical guidance for the rational design of delivery systems and functional surfaces. While mRNA therapies rely on LNP carriers, the adhesion efficiency of LNPs to biological or engineered surfaces is regulated by microscopic forces, the underlying mechanisms of which remained unclear. This study deeply integrates methodology with mechanistic interpretation by functionalizing AFM probes with -COOH, -OH, -NH₂, -PO₃H₂, and -CH₃ groups, enabling direct quantitative measurement and analysis of interfacial forces between these functional groups and mRNA-LNPs under physiological conditions. The research reveals that the competitive synergy between hydrogen bonding and electrostatic interactions determines adhesion behavior. Although -OH groups exhibit electrostatic repulsion with negatively charged mRNA-LNPs, their superior hydrogen-bonding capability results in the highest net attractive force, making them the most favorable binding sites.

The main contributions of this study are threefold. Theoretically, it systematically reveals the physicochemical mechanism by which functional groups regulate the interfacial behavior of mRNA-LNPs through hydrogen bonding and electrostatic interactions, deepening the understanding of nucleic acid nanocarrier transport processes. Methodologically, it establishes an effective approach using functionalized AFM probes to study interfacial interactions of complex nanobioparticles. In terms of application, it explicitly indicates that surfaces rich in -OH groups (such as cell membrane glycocalyx) are more prone to bind mRNA-LNPs, thereby providing clear molecular design principles for optimizing targeted delivery, designing antifouling medical devices, or developing efficient separation membrane materials. This work holds significant value for advancing mRNA-based pharmaceuticals and related biotechnologies.

First Author: Jingyi Wang

Corresponding Author: Professor Hongbo Zeng

Supporting information_APSUSC-D-24-02697R1

Probing the interaction mechanisms of lipid nanoparticle-enc