PUBLICATION
Peptide-Modified Lipid Nanoparticles Boost the Antitumor Efficacy of RNA Therapeutics
- Authors
- Zhao, G., Zeng, Y., Cheng, W., Karkampouna, S., Papadopoulou, P., Hu, B., Zang, S., Wezenberg, E., Forn-Cuní, G., Lopes-Bastos, B., Julio, M.K., Kros, A., Snaar-Jagalska, B.E.
- ID
- ZDB-PUB-250404-1
- Date
- 2025
- Source
- ACS nano : (Journal)
- Registered Authors
- Snaar-Jagalska, Ewa B.
- Keywords
- CD44, YAP/TAZ siRNA, lipid nanoparticles, patient-derived PDX, tumor targeting, zebrafish
- MeSH Terms
-
- Liposomes
- Male
- Peptides*/chemistry
- Animals
- Mice
- Nanoparticles*/chemistry
- Breast Neoplasms*/drug therapy
- Breast Neoplasms*/pathology
- Lipids*/chemistry
- Xenograft Model Antitumor Assays
- Female
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Antineoplastic Agents*/chemistry
- Antineoplastic Agents*/pharmacology
- RNA, Small Interfering*/chemistry
- RNA, Small Interfering*/genetics
- Humans
- Zebrafish
- PubMed
- 40176316 Full text @ ACS Nano
Citation
Zhao, G., Zeng, Y., Cheng, W., Karkampouna, S., Papadopoulou, P., Hu, B., Zang, S., Wezenberg, E., Forn-Cuní, G., Lopes-Bastos, B., Julio, M.K., Kros, A., Snaar-Jagalska, B.E. (2025) Peptide-Modified Lipid Nanoparticles Boost the Antitumor Efficacy of RNA Therapeutics. ACS nano. :.
Abstract
RNA therapeutics offer a promising approach to cancer treatment by precisely regulating cancer-related genes. While lipid nanoparticles (LNPs) are currently the most advanced nonviral clinically approved vectors for RNA therapeutics, their antitumor efficacy is limited by their unspecific hepatic accumulation after systemic administration. Thus, there is an urgent need to enhance the delivery efficiency of LNPs to target tumor-residing tissues. Here, we conjugated the cluster of differentiation 44 (CD44)-specific targeting peptide A6 (KPSSPPEE) to the cholesterol of LNPs via PEG, named AKPC-LNP, enabling specific tumor delivery. This modification significantly improved delivery to breast cancer cells both in vitro and in vivo, as shown by flow cytometry and confocal microscopy. We further used AKPC-siYT to codeliver siRNAs targeting the transcriptional coactivators YAP and TAZ, achieving potent gene silencing and increased cell death in both 2D cultures and 3D tumor spheroids, outperforming unmodified LNPs. In a breast tumor cell xenografted zebrafish model, systemically administered AKPC-siYT induced robust silencing of YAP/TAZ and downstream genes and significantly enhanced tumor suppression compared to unmodified LNPs. Additionally, AKPC-siYT effectively reduced proliferation in prostate cancer organoids and tumor growth in a patient-derived xenograft (PDX) model. Overall, we developed highly efficient AKPC-LNPs carrying RNA therapeutics for targeted cancer therapy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping