Delivery of polynucleotide-based therapeutics into target cells involves interactions with glycosaminoglycan chains that are located on cell membrane milieu. Mechanisms governing glycosaminoglycan-mediated changes in the nanoparticulate structures of polymer-polynucleotide complexes are unknown, and cannot be fully elucidated without atomistic level details of molecular interactions. We selected a representative nanoparticulate system consisting of a short interfering RNA (siRNA)-polyethylenimine complex, and performed all-atom molecular dynamics simulations with the prototypical glycosaminoglycan heparin. We monitored the binding between the complex constituents and the heparin, and identified key features contributing to the response of the siRNA nanoparticles to heparin. We observed three main metastable states that the siRNA nanoparticles might visit in the presence of heparin, which can be translated into different functional outcomes. By correlating our data with the widely different and seemingly contradictory roles previously assigned to glycosaminoglycans, this study provides unique insights into the discrepancies in the experimental literature concerning the role of glycosaminoglycans in the polymeric nanoparticle delivery.

基于多核苷酸的治疗剂向靶细胞的递送涉及与位于细胞膜环境上的糖胺聚糖链的相互作用。控制聚合物-多核苷酸复合物的纳米颗粒结构中糖胺聚糖介导的变化的机制尚不清楚，没有分子相互作用的原子级细节无法完全阐明。我们选择了由短干扰RNA（siRNA）-聚乙烯亚胺复合物组成的代表性纳米颗粒系统，并使用原型糖胺聚糖肝素进行了全原子分子动力学模拟。我们监测了复杂成分与肝素之间的结合，并确定了有助于siRNA纳米颗粒对肝素反应的关键特征。我们观察到三种主要的亚稳态，即在肝素存在下siRNA纳米颗粒可能会进入，这可以转化为不同的功能结果。通过将我们的数据与先前分配给糖胺聚糖的广泛不同且看似矛盾的作用相关联，本研究提供了关于糖胺聚糖在聚合物纳米颗粒递送中作用的实验文献中差异的独特见解。