2. Academic Validation
  3. Inhalable lipid nanoparticles for macrophage-specific STING gene editing to ameliorate pulmonary fibrosis

Inhalable lipid nanoparticles for macrophage-specific STING gene editing to ameliorate pulmonary fibrosis

  • Mol Ther. 2026 Jun 3;34(6):3353-3372. doi: 10.1016/j.ymthe.2026.03.003.
Yangeng Wang 1,  Xie Liu 1,  Wenzhe Xuan 1,  Wanling Huang 2,  Yueqiang Zhu 2,  Chengqiong Mao 3,  Yang Liu 4
Affiliations

Affiliations

  • 1 School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P.R. China.
  • 2 Key Laboratory of Biological Targeting Diagnosis, Therapy, and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 510180, P.R. China.
  • 3 Key Laboratory of Biological Targeting Diagnosis, Therapy, and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 510180, P.R. China. Electronic address: [email protected].
  • 4 School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P.R. China; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P.R. China; Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, P.R. China; Key Laboratory of Biomedical Materials of the Ministry of Education, South China University of Technology, Guangzhou 510006, P.R. China. Electronic address: [email protected].
PMID: 41795185 DOI: 10.1016/j.ymthe.2026.03.003
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited therapeutic options. The stimulator of interferon genes (STING) signaling pathway, particularly in alveolar macrophages, has been identified as a critical driver of fibrosis. However, achieving efficient and selective drug delivery to these pathogenic macrophages in the distal lung represents the major hurdle that hinders its clinical translation. To overcome this, we employed a systematic orthogonal screening strategy to develop a macrophage-targeted lipid nanoparticle (LNP) platform. Our optimized formulation, mCas9/gSting@DOPS, demonstrated an over 7-fold greater macrophage expression efficiency compared with commercial formulations and was engineered for precise in vivo Sting1 gene editing. This system leverages surface phosphatidylserine for selective uptake and encapsulates a CRISPR-Cas9 mRNA payload. Following inhalation, LNPs selectively accumulated in target macrophages within a murine model of pulmonary fibrosis. This targeted delivery resulted in effective Sting1 gene disruption, suppression of downstream STING signaling, and reduced secretion of pro-fibrotic cytokines. Functionally, treatment with mCas9/gSting@DOPS LNPs significantly attenuated Collagen deposition, alleviated alveolar collapse, and remodeled the fibrotic immune microenvironment. Notably, this therapeutic approach prolonged survival without evidence of systemic toxicity. Our findings establish that our orthogonally optimized LNP platform enables potent and clinically viable molecular therapy for IPF by efficiently targeting pulmonary macrophages.

Keywords

LNP; STING; idiopathic pulmonary fibrosis; inhalation; lipid nanoparticle; mRNA drug delivery.

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