Journal of controlled release : official journal of the Controlled Release SocietyNov 20, 2025

Using inhaled gene editing to target Spp1 for treating lung scarring

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 17, 2026

Abstract

Aerosolized inhalation of CaP/Cas9/PLGA nanoparticles leads to over 30% mutation frequency of the Spp1 gene in a mouse model.

Spp1 encodes osteopontin, which is associated with the progression of idiopathic pulmonary fibrosis (IPF).
Calcium phosphate and poly(lactic-co-glycolic acid) nanoparticles were developed for targeted delivery of the CRISPR/Cas9 system to the Spp1 gene.
The inhaled nanoparticles effectively cross mucosal barriers to reach fibrotic lung tissue and are taken up by lung cells without significant toxicity.
After internalization, the CRISPR system disrupts the Spp1 gene, leading to a marked decrease in osteopontin levels.
In a mouse model of bleomycin-induced pulmonary fibrosis, inhalation of these nanoparticles significantly reduced fibrosis and improved lung function.

Simplified

Secreted phosphoprotein 1 (Spp1) encoding osteopontin (OPN), a matrix cell protein with pro-inflammatory and pro-necrotic tissue properties, plays a crucial role in the onset and progression of idiopathic pulmonary fibrosis (IPF). In order to treat IPF by taking advantage of Spp1, we herein developed an inhalable system composed of calcium phosphate/ poly (lactic-co-glycolic acid) (PLGA) core-shell nanoparticles which are loaded with CRISPR/Cas9 system targeting Spp1 to investigate its therapeutic potential. Specifically, the plasmid encoding Cas9 and single-guide RNA (sgRNA) selectively targeting Spp1 gene was first condensed by calcium phosphate to form Cas9 complexes, which was then encapsulated by PLGA to formulate into a gene-editing inhalable delivery system (termed CaP/Cas9/PLGA). Interestingly, the aerosolized inhaled delivery of CaP/Cas9/PLGA nanoparticles results in the effective traverse of mucosal barriers to fibrotic lungs, where they are internalized by lung cells without inducing noticeable cytotoxicity. Following endo/lysosomal escape and gene expression of CRISPR system, the disruption of Spp1 gene by Cas9/sgRNA induces the mutation frequency exceeding 30 %, resulting in efficient down-regulation of OPN level. In a bleomycin-induced pulmonary fibrosis mouse model, the inhalation of aerosolized CaP/Cas9/PLGA complexes significantly attenuates fibrosis development and improves lung function with undetectable systemic toxicity. This current study defines an innovative inhalable gene-editing formulation and offers a promising gene therapy modality for treating IPF.

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Declaration of competing interest The authors declare no conflict of interest.

PubMed

Using inhaled gene editing to target Spp1 for treating lung scarring

Abstract

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