Abstract
The capacity of silencing genes makes small interfering RNA (siRNA) appealing for curing fatal diseases. However, the naked siRNA is vulnerable to and degraded by endogenous enzymes and is too large and too negatively charged to cross cellular membranes. An effective siRNA carrier, PMAL (poly(maleic anhydride-alt-1-decene) substituted with 3-(dimethylamino) propylamine), has been demonstrated to be able to assist siRNA transmembrane by both experiments and molecular simulation. In the present work, the mechanism of siRNA transmembrane assisted by PMAL was studied using steered molecular dynamics simulations based on the martini coarse-grained model. Here two pulling rates, i.e., 10−6 and 10−5 nm·ps−1, were chosen to imitate the passive and active transport of siRNA, respectively. Potential of mean force (PMF) and interactions among siRNA, PMAL, and lipid bilayer membrane were calculated to describe the energy change during siRNA transmembrane processes at various conditions. It is shown that PMAL-assisted siRNA delivery is in the mode of passive transport. The PMAL can help siRNA insert into lipid bilayer membrane by lowering the energy barrier caused by siRNA and lipid bilayer membrane. PMAL prefers to remain in the lipid bilayer membrane and release siRNA. The above simulations establish a molecular insight of the interaction between siRNA and PMAL and are helpful for the design and applications of new carriers for siRNA delivery.
Highlights
Small interfering RNA has attracted broad interests in exploring its potential application in gene therapy for fatal diseases, including viral infections and cancers [1,2,3,4]
It is shown that the contact area increases when the naked Small interfering RNA (siRNA) enters the membrane, and reaches highest value when siRNA totally is imbedded into the membrane
The active and passive transport of siRNA were discussed using steered molecular dynamics simulations based on the martini coarse-grained model
Summary
Small interfering RNA (siRNA) has attracted broad interests in exploring its potential application in gene therapy for fatal diseases, including viral infections and cancers [1,2,3,4]. The naked siRNA, is vulnerable to endogenous enzyme and degraded. It is too large (~13 kDa) and too negatively charged to cross cellular membranes. A safe and effective delivery protocol is pursued for the therapeutic application of siRNA [5,6]. Non-viral siRNA delivery carriers—including liposome, lipid-like materials, polymers, and nanoparticles—have been extensively investigated in recent years due to their proven advantages, such as low immune response, safety, and ease of synthesis [9,10].
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