Year: 2025
Type: article
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.
Source: Nature Communications
Authors: 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
Institutions: Harvard University, Wyss Institute for Biologically Inspired Engineering, University of North Texas, University of North Texas Health Science Center, The University of Texas at Dallas, Harvard–MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, University of California Davis Medical Center, UC Davis Health
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1120188257, G1915563957, G2383814189, G2390440901, G2541397611, Tumor-associated macrophage reprogramming through PARP14 inhibition in muscle-invasive bladder cancer, G401456990, G4534695922, G4561983161, G750101164, G8282653809, G9000011189, G9000011884, G9000037087, G9000075951, G918485426
OpenAlex ID: W4416469469