Systematic design of DMBT1-derived peptides correlating physicochemical properties and sequence motifs with siRNA delivery and efficacy in cancer therapy
Year: 2025
Type: article
Abstract: BACKGROUND: Molecules driving the cancer process are frequently difficult to target with traditional small-molecule drugs. Small interfering RNAs (siRNAs) offer high specificity, but their clinical translation is hindered by inefficient delivery and rapid degradation. We previously identified DMBT1-derived cell-penetrating peptides (CPPs) that encapsulate siRNA and improve serum stability in vitro. METHODS: We designed 37 DMBT1-derived peptides using a rational, high-throughput pipeline to enhance siRNA encapsulation, stability, and delivery. Binding, uptake, and silencing were assessed in A375 and MCF7 cells. Regression and motif discovery analyses were applied to link peptide physicochemical features with encapsulation efficiency, serum stability, and gene silencing. FINDINGS: -siRNA and significantly reducing A375 proliferation in vitro. In female NOG CIEA mice xenografts, HE25 suppressed tumour growth, while repeated intravenous dosing in BALB/c mice confirmed biosafety. INTERPRETATION: Targeted optimisation combined with motif-based design establishes a framework for developing next-generation CPPs. The identification of a conserved motif driving efficient delivery highlights new opportunities for advancing siRNA therapeutics in cancer and beyond. FUNDING: This work was supported by Novo Nordisk Foundation, Villum Foundation, Lundbeck Foundation, A.P. Møller Foundation, Dagmar Marshalls Foundation, Neye Foundation, Fabrikant Einar Willumsens Mindelegat, and Direktør Michael Hermann Nielsens Mindelegat.
Source: EBioMedicine
Institutions: University of Southern Denmark, Odense University Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,780
Awards: G6776880988, G7334130110
OpenAlex ID: W4415432502