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 () and Bijay Singh ()
Additional contact information
Kyung Soo Park: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Vineeth Chandran Suja: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Jayoung Kim: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Danika Rodrigues: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Malini Mukherji: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Maithili Joshi: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Yongsheng Gao: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Michael Griffith Bibbey: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Jeong-Won Choi: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Rick Liao: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Morgan E. Janes: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Metecan Erdi: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Andrés Da Silva Candal: Health Research Institute of Santiago de Compostela, Clinical Neurosciences Research Laboratory, Clinical University Hospital
David L. Cameron: UC Davis Health System, Neurology Department, Stem Cell Program and Gene Therapy Center
Julian A.N.M. Halmai: UC Davis Health System, Neurology Department, Stem Cell Program and Gene Therapy Center
Kyle D. Fink: UC Davis Health System, Neurology Department, Stem Cell Program and Gene Therapy Center
Samir Mitragotri: Harvard University, John A. Paulson School of Engineering and Applied Sciences
Bijay Singh: Harvard University, John A. Paulson School of Engineering and Applied Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65185-1

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