Cytidinyl/Cationic Lipids-siRNA Delivery Silences MYC to Reprogram Macrophages and Circadian Rhythm for Cancer Treatment

Mar 17, 2026Molecular pharmaceutics

Using special lipids to deliver siRNA that silences MYC, changes immune cells and body clock to help treat cancer

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

siMYC@Dmix achieved approximately 77% mRNA silencing in Lewis Lung Carcinoma cells.

Treatment with siMYC@Dmix significantly inhibited tumor growth in C57BL/6J mice.
The therapy induced a shift in macrophage polarization toward the M1 phenotype.
Increased infiltration and cytotoxic function of CD8 T cells were observed.
Natural killer (NK) cell activity was enhanced following treatment.
Maturation of dendritic cells was also noted as a result of the therapy.
Silencing MYC restored expression of core circadian clock genes.

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Nonsmall cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, withoncogene overexpression driving tumor progression and immunosuppression. MYC has been deemed "undruggable" for a long period, and the impact of its silencing on the tumor associated macrophage polarization and circadian rhythm remains unexplored. Here, we developed a lipid nanoparticle (siMYC@Dmix) composed of cytidinyl lipid (DNCA), gemini-like cationic lipid (CLD), and DSPE-PEG2000 for efficientsiRNA delivery. In vitro, siMYC@Dmix showed robust cellular uptake, lysosomal escape, and ∼77%mRNA silencing in Lewis Lung Carcinoma (LLC) cells. In vivo, siMYC@Dmix treatment significantly inhibited tumor growth in C57BL/6J mice and induced a profound remodeling of the tumor immune microenvironment. This was characterized by a shift in macrophage polarization toward the M1 phenotype, increased infiltration and cytotoxic function of CD8T cells, enhanced natural killer (NK) cell activity, and maturation of dendritic cells (DCs). Crucially,silencing restored the expression of core circadian clock genes. Our findings unveil a promising RNAi-based strategy that concurrently targets-driven tumorigenesis, corrects circadian dysfunction, and reinstates antitumor immunity, presenting a multifaceted therapeutic approach for NSCLC. MYC MYC MYC MYC MYC +

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Cytidinyl/Cationic Lipids-siRNA Delivery Silences MYC to Reprogram Macrophages and Circadian Rhythm for Cancer Treatment

Abstract

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