The ERBB2 is one of the most studied genes in oncology for its significant role in human malignancies. The metastasis-associated properties that facilitate cancer metastasis can be enhanced by activating the ERBB2 receptor signaling pathways. Additionally, therapeutic resistance is conferred by ERBB2 overexpression via receptor-mediated antiapoptotic signals. Several ERBB2-blocking techniques have the effect of overexpressed ERBB2, and several of them have passed clinical trials for use as therapies. Small interfering RNAs (siRNA), which have the potential to silence genes, are attractive for treating such fatal malignancies. In this study, we rationally designed a siRNA molecule targeting the human ERBB2 gene. The selection process involved identifying a shared region among all ERBB2 transcripts for siRNA design. The ultimate siRNA candidate was chosen through rigorous evaluation using contemporary algorithms, considering off-target similarities, examination of thermodynamic properties, and analysis using molecular dynamics (MD) simulations. Further, we opted for cell-penetrating peptides (CPP) and RNA aptamer as carriers for the siRNA. Employing both steered MD simulations and traditional MD simulations, we investigated how these carriers facilitate siRNA delivery. Experimental confirmation revealed the stability of the selected carriers and siRNA on the lipid bilayer. The designed siRNA molecule and the simulations present a potential alternative therapeutic strategy against human ERBB2. This contributes to advances in developing and utilizing innovative carriers for the delivery of siRNA, enhancing the potential for therapeutic applications.

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http://dx.doi.org/10.1016/j.compbiomed.2025.109663DOI Listing

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