Materials today (Kidlington, England)Jul 2, 2026

Biodegradable fat-based particles for editing genes in the brain through spinal fluid injection

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 3, 2026

Abstract

P3B lipid nanoparticles achieved 14.8% on-target correction in a mouse model for gene editing.

P3B lipid nanoparticles (LNPs) effectively delivered Cas9 mRNA/sgRNA, resulting in robust tdTomato expression in neurons and astrocytes across multiple brain regions.
Editing efficiency with P3B-LNPs surpassed the clinical benchmark DLin-MC3-DMA.
P3B-LNPs facilitated adenine base editing, restoring luciferase expression with minimal off-target effects.
Enhanced tolerability of P3B-LNPs was observed, showing reduced inflammatory responses compared to MC3.
The study highlights the potential of biodegradable lipid nanoparticles for safe and efficient gene editing in the central nervous system.

Simplified

Messenger RNA (mRNA)-based nonviral delivery of gene editors offers transformative potential for therapeutic genome editing in neurological diseases, but efficient and safe delivery to the brain remains a formidable challenge due to the restrictive blood-brain barrier. Intrathecal administration provides a clinically validated route to bypass this barrier, yet the design principles for biodegradable lipid nanoparticles (LNPs) optimized for central nervous system (CNS) delivery remain poorly defined. Here, we synthesized a 200-member combinatorial library of structurally diverse, biodegradable ionizable lipids using the Passerini three-component reaction. High-throughput in vivo screening identified P3B, a lead lipid incorporating degradable linkages and optimized ionizable head groups, which enables potent and well-tolerated intrathecal mRNA delivery. In Ai9 reporter mice, P3B-LNPs encapsulating Cas9 mRNA/sgRNA induced robust and widespread tdTomato expression in neurons and astrocytes across multiple brain regions, achieving substantially higher editing efficiency than the clinical benchmark DLin-MC3-DMA (MC3). In LumA reporter mice, P3B-LNPs mediated efficient adenine base editing, restoring luciferase expression throughout the brain with 14.8% on-target correction and minimal off-target activity. Compared with MC3, P3B-LNPs exhibited enhanced tolerability, with attenuated inflammatory responses and a safety profile supportive of repeated dosing. These findings establish P3B-LNPs as a potent, safe, and biodegradable platform for genome editing in the brain and underscore the power of combinatorial lipid chemistry and high-throughput in vivo screening to accelerate the development of next-generation LNPs for CNS-targeted mRNA therapeutics.