Abstract：
The surface physiochemical properties of nanomedicine play a crucial role in modulating biointerfacial reactions in sequential biological compartments, accordingly accomplishing the desired programmed delivery scenario to intracellular targets. PEGylation, which involves modifying the surface with a layer of poly(ethylene glycol), has been validated as an effective strategy for minimizing adverse biointerfacial interactions. However, it has also been observed to impede cellular uptake and intracellular trafficking activities. To address this dilemma, we propose a dynamic surface chemistry approach that actively prevents non-specific reactions in systemic circulation, while readily facilitating cellular uptake by converting into a highly cytomembrane-adhesive state. Moreover, the surface becomes more adhesive to endolysosomal membranes, enabling translocation into the cytosol. In this study, PEGylated mRNA delivery nanoparticulates were tethered with charge-reversible polymers to create dynamic surroundings through click chemistry. Importantly, the dynamic surroundings exhibited negative charges under physiological conditions (pH 7.4). This property prevented degradation by anionic nucleases and structural disassembly induced by endogenous charged biological species. Consequently, the nanoparticles exhibited appreciable stealth function, effectively managing the first pass effect, leading to prolonged blood retention and improved bioavailabilities at targeted cells. Furthermore, the dynamic surroundings shifted towards relatively positive charges in the tumor microenvironment (pH 6.8). As a result, the nanoparticles were more likely to be taken up by tumors due to their electrostatic affinities towards polyanionic cytomembranes. Eventually, the internalized mRNA nanomedicine transformed responsive to the surrounding microenvironment into highly positive charges within acidic endolysosomes (pH 5.0), exerting explosive disruptive potencies on the endolysosomal structures, thus facilitating translocation of mRNA from the digestive endolysosomes into the targeted cytosol. Notably, the dynamic surroundings also reduced the immunogenicity of naked mRNA due to their stealthy properties and rapid endolysosomal translocation functions. In summary, our proposed unique triple-transformable dynamic surface chemistry provided an intriguing delivery scenario that overcomes sequential biological barriers, contributing to efficient expression of the encapsulated mRNA at targeted tumors.
摘要：
纳米药物的表面理化性质在调节连续生物区室中的生物界面反应中起着至关重要的作用。相应地完成所需的向细胞内靶标的程序化递送方案。聚乙二醇化,其中包括用一层聚乙二醇修饰表面，已被验证为最小化不利的生物界面相互作用的有效策略。然而,它也被观察到阻碍细胞摄取和细胞内运输活动。为了解决这个难题，我们提出了一种动态表面化学方法，可以积极防止体循环中的非特异性反应，同时容易通过转化为高度细胞膜粘附状态来促进细胞摄取。此外，表面变得更加粘附于内溶酶体膜，使易位进入细胞质。在这项研究中,PEG化的mRNA递送纳米颗粒用电荷可逆聚合物束缚以通过点击化学产生动态环境。重要的是,在生理条件（pH7.4）下，动态环境显示负电荷。这种特性防止了阴离子核酸酶的降解和内源性带电生物物种诱导的结构分解。因此,纳米粒子表现出明显的隐身功能，有效管理第一关效应，导致延长的血液滞留和提高靶细胞的生物利用度。此外，动态环境向肿瘤微环境（pH6.8）中的相对正电荷转移。因此,由于纳米颗粒对聚阴离子细胞膜的静电亲和力，它们更容易被肿瘤吸收。最终,内化的mRNA纳米药物响应于周围的微环境转化为酸性内溶酶体（pH5.0）内的高度正电荷，在内溶酶体结构上施加爆炸性的破坏性效力，从而促进mRNA从消化内溶酶体转位到靶向的胞质溶胶中。值得注意的是,动态环境还降低了裸mRNA的免疫原性，因为它们具有隐秘的特性和快速的内溶酶体易位功能。总之,我们提出的独特的三重可转化动态表面化学提供了一个有趣的交付方案，克服了顺序生物障碍，有助于在靶向肿瘤中有效表达包封的mRNA。
