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Preprint WatchMildAugust 26th, 2026

Lipid anchor engineering controls cell-penetrating arginine-rich peptide presentation for efficient siEGFR liposomal delivery to triple-negative breast cancer cells

Bialecki, P.; Braccia, S.; Makowski, T.; Piorecka, K.; Falcigno, L.; Bellavita, R.; Falanga, A.; Bryszewska, M.; Robaszkiewicz, A.; Galdiero, S.; Pedziwiatr-Werbicka, E.

A peptide-functionalised cationic liposome using cholesterol-anchored nona-arginine delivers EGFR-directed siRNA to triple-negative breast cancer cells, with lipid anchor engineering controlling peptide presentation and delivery efficiency.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The Claidex record holds one EGFR failure, bg-60366-egfr-cdac-nsclc-strategic-shutdown, a Phase 1 EGFR chimeric degrader in EGFR-mutant lung cancer that ended by sponsor decision rather than by a negative efficacy readout, so the flag is MILD and carries no efficacy prior. The more relevant distinction is population rather than target: that program addressed EGFR-mutant disease, while this preprint addresses triple-negative breast cancer, where EGFR is overexpressed but rarely mutated and where EGFR-directed agents have historically underperformed. A delivery platform improves exposure and does not resolve whether EGFR knockdown is the driver in that setting, so the delivery result and the target hypothesis need separate evidence.

Abstract excerpt

Understanding the physicochemical factors that govern siRNA nanocarrier assembly is essential for the rational design of effective delivery systems. By optimizing various lipid compositions, cholesterol content and PEG length we created a peptide-functionalized cationic liposomal platform made of DOPE/TAP lipids with cholesterol-anchored nona-arginine (R9-Chol) for siRNA complexation, intracellular transport and effective silencing of the target EGFR gene. Analysis of {zeta}-potential and dynamic light scattering allowed to rationally design formulation of stable, monodisperse nanoscale lipoplexes with a positive surface charge. With fluorescence polarization, circular dichroism and agarose gel electrophoresis we found an optimal siRNA:liposome complexation ratio of 1:77, which protected siRNA from ribonuclease-mediated degradation. Morphological imaging confirmed a shift from discrete vesicular structures to organized multilamellar lipoplexes, consistent with electrostatically driven self-assembly. In cellular studies, the optimized nanocarrier promoted efficient uptake of fluorescent siRNA in MDA-MB-231 cells and achieved functional delivery of anti-EGFR, leading to substantially reduced expression of the target gene at both transcript and protein levels. This work offers mechanistic understanding of peptide-assisted lipid:siRNA assembly and positions R9-functionalized DOPE/TAP liposomes as a promising platform for siRNA delivery.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.