On September 28, 2026 Silexion Therapeutics Corp. (NASDAQ: SLXN) ("Silexion" or the "Company"), a clinical-stage biotechnology company pioneering RNA interference (RNAi) therapies for KRAS-driven cancers, reported positive new findings from an ongoing translational study evaluating the cellular uptake and gene-silencing mechanism of its lead candidate, SIL204. The study, part of the Company’s translational research program supporting its Phase 2/3 clinical development, demonstrates that SIL204 effectively harnesses naturally occurring circulating lipoproteins to achieve cellular internalization and drive potent, dose-dependent knockdown of mutant KRAS oncogene expression in cancer cells.
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Extending oligonucleotide delivery beyond the liver represents a major frontier in RNAi therapeutics.1 The newly reported findings demonstrate that SIL204 is designed to utilize native lipid transport pathways to achieve intracellular delivery in tumor cells. In the study, conducted in a carrier-free, non-transfection assay without synthetic transfection reagents, human KRAS-driven cancer cells treated with SIL204 exhibited robust, dose-dependent gene silencing in the presence of standard physiological serum lipids. In contrast, depletion of serum lipids resulted in a statistically significant reduction in gene-knockdown efficiency (P < 0.001), confirming that circulating lipoproteins play a direct, functional role in mediating SIL204 cellular uptake and oncogenic silencing.2
Importantly, the addition of exogenous human low-density lipoprotein (LDL) did not alter gene-silencing potency compared to complete serum alone. This observation indicates that endogenous levels of circulating lipoproteins present under normal physiological conditions are already sufficient to support efficient cellular uptake and target knockdown, eliminating the need for external lipid supplementation or artificial carrier vehicles.
"These findings represent an essential mechanistic milestone in our translational characterization of SIL204," said Dr. Mitchell Shirvan, Chief Scientific and Development Officer of Silexion Therapeutics. "One of the central design objectives of SIL204 was to engineer an oligonucleotide construct capable of entering target cancer cells efficiently while maintaining biological integrity. By demonstrating that SIL204 engages native lipoprotein pathways for cellular entry without requiring synthetic transfection reagents, we have demonstrated a fundamental biological mechanism that underpins its intracellular delivery. These results establish that standard physiological lipid levels are sufficient to enable potent target silencing, providing crucial mechanistic support as we advance our ongoing pharmacokinetic and biodistribution evaluations. Because the LDL receptor has been shown in vivo to be upregulated in cancer cells compared to healthy cells3, this represents an endogenous targeted delivery mechanism that is envisioned to improve the side effect profile in a clinically meaningful way."
"Demonstrating this natural uptake mechanism reinforces our broader clinical development strategy and our Integrated Treatment Regimen for SIL204," said Ilan Hadar, Chairman and Chief Executive Officer of Silexion Therapeutics. "While our Phase 2/3 clinical program in locally advanced pancreatic cancer targets the primary tumor, our vision has always encompassed systemic administration to address micro-metastases and distant disease spread. Confirming that SIL204 can leverage the body’s own lipid transport network for cellular entry provides a strong mechanistic foundation for systemic subcutaneous delivery. As we continue active site initiation and patient screening in our clinical program, these translational insights further validate the unique therapeutic potential of our next-generation RNAi platform."
The findings emerge as Silexion continues translational characterization of SIL204 alongside clinical trial site initiation at Tel Aviv Sourasky Medical Center and regulatory clearances in Germany. Additional preclinical evaluations, including in vivo pharmacokinetic (PK), cellular uptake kinetics, and tissue biodistribution studies, are currently underway to further characterize the correlation between lipoprotein association, LDLR pathway engagement, systemic exposure, and anti-tumor activity in vivo.
(Press release, Silexion Therapeutics, SEP 28, 2026, View Source [SID1234671130])