ArticleACS applied bio materials2026
LNP-Mediated CF10 Delivery Selectively Enhances Potency to Colorectal Cancer Cells and Preserves the TS/Top1 Dual Targeting Mechanism.
Article in ACS applied bio materials, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Lipid nanoparticles (LNPs) are extensively utilized in nucleic acid delivery for therapeutic applications because of their biocompatibility and protection of the nucleic acid cargo from degradation during in vivo transport. The nanoscale DNA-based fluoropyrimidine polymer CF10 shows strong efficacy advantages relative to conventional fluoropyrimidine drugs such as 5-fluorouracil (5-FU). In principle, LNP-mediated delivery of CF10 could further enhance its efficacy advantage relative to 5-FU by increasing plasma stability and promoting cell uptake. However, the anticancer activity of CF10 relies on the release of active nucleotides, and it is not clear that LNP-mediated delivery of CF10 preserves dual targeting of thymidylate synthase (TS) and DNA topoisomerase 1 (Top1). This study proposes the incorporation of CF10 into LNPs using chaotic mixing of lipid compositions in a microfluidic chip. Biophysical characterization revealed homogeneous LNP formation with size 80-200 nm in diameter and a zeta-potential of -15 mV, dependent on CF10 concentration. LNPs were stable (tested in PBS) over 4 weeks. In vitro studies showed that LNP formulation increased CF10 uptake specifically into cancer cells, while an immortalized nonmalignant intestinal cell line did not show increased uptake of CF10:LNPs. CF10:LNPs initially colocalized with endosomes, followed by primarily lysosome colocalization at 48 h. CF10:LNPs displayed increased cytotoxicity to cancer cells relative to free CF10, proportional to increased cell uptake. Potent inhibition of TS was achieved consistently with nuclease-mediated release of FdUMP from CF10 in lysosomes. CF10:LNPs also efficiently induced Top1 cleavage complex formation, consistent with perturbation of cellular dNTP pools similar to free CF10. These findings indicate that CF10:LNPs display enhanced anticancer activity relative to free CF10 and preserve CF10's unique TS/Top1 dual targeting mechanism.
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