Multiscale red blood cell hitchhiking for targeted deep tissue gene delivery in lungs
The clinical impact of gene therapies is constrained by poor delivery to target tissues beyond the liver after intravenous administration. Current molecular targeting strategies, such as capsid engineering or gene-carrier surface modification, have achieved only limited success due to their inability to overcome the hierarchical barriers from injection to deep tissue transduction. Here, we introduce a Multiscale Approach using RBC-mediated hitchhiking and Vascular Endothelium Leakage (MARVEL), which integrates red blood cell hitchhiking with VEGF-induced vascular permeabilization to enhance accumulation and penetration of cargoes. Using adeno-associated viruses (AAVs) as a model, MARVEL markedly increases AAV localization in the lungs, improves endothelial transcytosis, and enables gene expression in deeper tissue layers while maintaining a favorable safety profile. We further demonstrate that MARVEL can be adopted into an in situ hitchhiking approach, bypassing the need for ex vivo formulation. MARVEL provides a scalable strategy to address long-standing delivery challenges in gene therapy.
Authors
- Bijay Singh (ORCID: https://orcid.org/0000-0002-3125-3655)
- Kyle D. Fink (ORCID: https://orcid.org/0000-0002-0235-5038)
- Julian Halmai (ORCID: https://orcid.org/0000-0002-2642-0367)
- Michael Griffith Bibbey (ORCID: https://orcid.org/0009-0002-9449-5384)
- Kyung Soo Park (ORCID: https://orcid.org/0000-0003-1339-5673)
- Vineeth Chandran Suja (ORCID: https://orcid.org/0000-0002-3406-7655)
- Maithili Joshi (ORCID: https://orcid.org/0000-0002-1871-4234)
- Rick Liao (ORCID: https://orcid.org/0000-0002-4780-161X)
- David Cameron
- Danika Rodrigues (ORCID: https://orcid.org/0000-0001-8648-5472)
- Morgan E. Janes
- Metecan Erdi (ORCID: https://orcid.org/0000-0001-9267-654X)
- Samir Mitragotri (ORCID: https://orcid.org/0000-0002-2459-8305)
- Jayoung Kim (ORCID: https://orcid.org/0000-0002-5010-8090)
- Jeong-Won Choi (ORCID: https://orcid.org/0000-0001-8287-450X)
- Yongsheng Gao (ORCID: https://orcid.org/0000-0002-2347-1855)
- Malini Mukherji
- Andrés Da Silva Candal
Institutions
- University of North Texas (US)
- Harvard University (US)
- The University of Texas at Dallas (US)
- University of North Texas Health Science Center (US)
- Harvard University Press (US)
- University of North Texas System (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- Dana-Farber/Harvard Cancer Center (US)
- UC Davis Health (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1038/s41467-025-65185-1
- Citations
- 2
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 3.63
Funders
- National Science Foundation
- Dana-Farber/Harvard Cancer Center
- National Institutes of Health
- Instituto de Salud Carlos III
- National Cancer Institute