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  3. Genome-Wide CRISPR Screen Reveals PIK3CA Inhibition Enhances Lipid Nanoparticle-Mediated siRNA Delivery

Genome-Wide CRISPR Screen Reveals PIK3CA Inhibition Enhances Lipid Nanoparticle-Mediated siRNA Delivery

  • Adv Sci (Weinh). 2025 Dec 7:e17617. doi: 10.1002/advs.202517617.
Wenhan Wang 1 2,  Kangfu Chen 2 3,  Zongjie Wang 1 2
Affiliations

Affiliations

  • 1 Chan Zuckerberg Biohub Chicago, Chicago, IL, 60607, USA.
  • 2 Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, 60208, USA.
  • 3 School of Integrated Circuits and Electronics, Beijing Institute of Technology, Beijing, 100081, P. R. China.
PMID: 41354630 DOI: 10.1002/advs.202517617
Abstract

Lipid nanoparticles (LNPs) are useful carriers for therapeutic siRNA delivery, yet their clinical efficacy remains constrained by insufficient cellular uptake. Here, using a genome-wide CRISPR knockout screen, multiple genetic modulators of LNP uptake is uncovered, with PIK3CA emerging as a top druggable target. Pharmacologic inhibition of PIK3CA with BAY1082439 - a clinically evaluated small molecule - significantly enhances LNP uptake, siRNA delivery, and gene silencing across diverse epithelial Cancer cell lines in vitro. Co-administration of BAY1082439 with siRNA-loaded LNPs also better suppressed tumor growth and reduced liver inflammation in vivo, respectively. These findings establish PIK3CA inhibition as a broadly applicable strategy to boost LNP-mediated RNA interference and highlight the promise of combining functional genomics with nanomaterials to advance RNA-based therapeutics.

Keywords

CRISPR; cancer treatment; functional genomics; inflammatory diseases; lipid nanoparticles, siRNA.

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