FUSOGENIC INTRACELLULAR DELIVERY OF CRISPR/CAS9 USING MESOPOROUS SILICA-LIPID HYBRID NANOPARTICLES

Abstract

The efficient delivery of CRISPR/Cas9 ribonucleoproteins (RNPs) remains a critical challenge for realizing their therapeutic potential. Here, we introduce a novel fusogenic nanoparticle system inspired by cell membrane fusion mechanisms, designed to deliver CRISPR RNPs directly into the cytosol while avoiding endosomal degradation. The system employs mesoporous silica nanoparticles (MSNs) coated with a lipid bilayer containing fusogenic and ionizable lipids. These nanoparticles exhibit pH-responsive properties, enabling selective RNP release in the acidic tumor microenvironment. In vitro and in vivo studies demonstrate efficient genome editing, tumor-specific targeting, and significant therapeutic efficacy with minimal off-target effects. This platform represents a versatile and precise approach to CRISPR-based gene editing, advancing personalized cancer therapy.