Multiscale red blood cell hitchhiking for targeted deep tissue gene delivery in lungs
- Kyung Soo Park
- Vineeth Chandran Suja
- Jayoung Kim
- Danika Rodrigues
- Malini Mukherji
- Maithili Joshi
- Yongsheng Gao
- Michael Griffith Bibbey
- Jeong-Won Choi
- Rick Liao
- Morgan E. Janes
- Metecan Erdi
- Andrés Da Silva Candal
- David L. Cameron
- Julian A.N.M. Halmai
- Kyle D. Fink
- Samir Mitragotri
- Bijay Singh
2025-11-21
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.