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

## TL;DR

A CRISPR screen found that inhibiting the PIK3CA gene improves the delivery of siRNA via lipid nanoparticles, enhancing treatment effectiveness in cancer cells and animal models.

## Contribution

Identifies PIK3CA as a druggable target to enhance LNP-mediated siRNA delivery through genome-wide CRISPR screening.

## Key findings

- Pharmacologic inhibition of PIK3CA with BAY1082439 significantly enhances LNP uptake and gene silencing in epithelial cancer cells.
- Co-administration of BAY1082439 with siRNA-loaded LNPs suppresses tumor growth and reduces liver inflammation in vivo.

## 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.

A genome‐wide CRISPR screen and identifies PIK3CA as a key regulator of lipid nanoparticle (LNP) uptake is performed. Modulating PIK3CA with small‐molecule inhibitor BAY1082439 enhanced LNP uptake, siRNA delivery, and gene silencing in a variety of epithelial cells, and improved therapeutic outcomes in vivo. The work presents PIK3CA inhibition as a promising strategy to boost LNP‐based RNA therapeutics.