One shot to heal: CRISPR nanotherapy repairs damaged lungs and tackles long COVID

A research team has developed a single-dose CRISPR-CasRx nanotherapy targeting the host enzyme cathepsin L (referred to as SCNC) that not only reduces SARS-CoV-2 viral load during acute infection but also promotes lung repair in a hamster model of post-acute sequelae of COVID-19 (PASC), or long COVID. The findings, recently published in Nano Research, open a promising avenue for treating long-term respiratory damage caused by COVID-19.

PASC affects an estimated 10-20% of COVID-19 survivors, with symptoms including chronic cough, shortness of breath, and even lung fibrosis that can persist for months or longer. “Surprisingly, even patients with mild initial infections can go on to develop significant lung damage,” said Dr. Qianben Wang, Banks Anderson, Sr. Distinguished Professor at Duke University School of Medicine. “There are currently no effective therapies for reversing these changes in the lungs.”

The team’s innovative strategy focuses on cathepsin L (Ctsl), a host protease that facilitates viral entry and contributes to post-viral lung inflammation and impaired tissue repair. Using lung-targeted lipid nanoparticles (LNPs), they delivered CasRx mRNA and a guide RNA designed to knock down Ctsl expression.

In the Syrian golden hamster model, animals receiving the CRISPR nanotherapy (SCNC) during acute infection showed a 1,000-fold reduction in viral load, comparable to the FDA-approved antiviral Paxlovid. More strikingly, at 31 days post-infection—a key time point for diagnosing PASC—SCNC-treated animals exhibited significantly reduced alveolar epithelial hyperplasia and lung inflammation.

“Single-cell RNA sequencing revealed that SCNC not only suppressed inflammatory cell infiltration but also promoted the repair of alveolar structures by driving type II alveolar epithelial (AT2) cells to differentiate into type I alveolar epithelial (AT1) cells, which are critical for gas exchange,” explained Dr. Victor Jin, Professor and Linda T. and John A. Mellowes Endowed Chair of Bioinformatics and Data Analytics at the Medical College of Wisconsin.

The treatment was well tolerated, with no signs of toxicity in major organs. This dual action—antiviral and regenerative—positions SCNC as a potential therapeutic for both acute and long-term COVID-19 complications.

“This study highlights the promise of targeting host factors rather than the virus itself,” noted Dr. Shan-Lu Liu, Professor at The Ohio State University. “It could provide broader protection against emerging variants and a much-needed option for patients with long COVID.”

Looking ahead, the team plans to evaluate SCNC in larger animal models and explore its potential for clinical translation. “Our ultimate goal is to bring this therapy closer to patients and to expand its application to other respiratory diseases involving epithelial injury,” said Dr. Yizhou Dong, Mount Sinai Endowed Professor in Nanomedicine at Icahn School of Medicine at Mount Sinai.

The study was led by Zhifen Cui, Ph.D., a research scientist in the Department of Pathology at Duke University School of Medicine and a member of Dr. Qianben Wang’s laboratory. Other contributors include Rebecca Bacon, Yue Zhao, Jeffrey I. Everitt, Jiaoti Huang, and Hongyan Wang from the Department of Pathology, Duke University School of Medicine; Tianxiang Liu from the Medical College of Wisconsin Cancer Center; Jingyue Yan from the Icahn School of Medicine at Mount Sinai; and Lingye Chen from the Department of Medicine, Duke University School of Medicine.

This work was supported by the Department of Pathology, Duke University School of Medicine and the National Institute of General Medical Sciences.

About Nano Research

Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.