CHARIOT-AAV: Conjugation of diverse vectors to adeno-associated viruses for delivery of large genes
Year: 2026
Type: preprint
Abstract: Systemic, tissue-specific delivery of large transgenes exceeding the packaging capacity of adeno-associated viruses (AAVs) remains a key translational challenge for molecular therapeutics. Vectors with larger capacities, such as lentiviral vectors (LVVs) and lipid nanoparticles (LNPs), often lack adjustable, tissue-specific tropisms. Here we report CHARIOT-AAV (Crosslinked Hybrid Architectures for Robust, Interchangeable, and Organ-specific Targeting with AAV), a platform where diverse delivery vectors are conjugated to AAVs, thereby achieving tissue-specific tropism of AAVs and expanded cargo capacity. AAV-AAV conjugates packaging split SpCas9 constructs in AAV.CAP-B10 capsids demonstrate a ~2-fold increase in brain gene editing efficiency over unconjugated AAV cocktails after intravenous injection. In addition to AAV-AAV conjugates, AAV-LVV and AAV-LNP conjugates achieve AAV-guided delivery of genetic payloads to target cells. Furthermore, AAV-LNP conjugates enable systemic delivery of mRNAs to brain endothelial cells. CHARIOT-AAV thus provides a modular platform for systemic, tissue-specific delivery of diverse therapeutics beyond the limits of individual vectors.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, Simons Foundation, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Fujifilm Corporation, Honjo International Scholarship Foundation, National Institutes of Health, Materials Research Science and Engineering Center, Harvard University, Multidisciplinary University Research Initiative, Simons Center for the Social Brain, Massachusetts Institute of Technology, McGovern Institute for Brain Research, Massachusetts Institute of Technology, National Institute of Mental Health, Division of Materials Research, Army Research Office
Awards: G1425446948, G1495680632, G3128876285, G318041215, G3202401936, G391170236, G7452299184, MIT Materials Research Science and Engineering Center - Full Proposal, G9000073878, G9000272116, Early developmental mechanisms of Rett Syndrome, Fusion of nanomagnetic and viral tools to interrogate brain-body circuits
OpenAlex ID: W7154494741
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