{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:05:21Z","timestamp":1782281121392,"version":"3.54.5"},"posted":{"date-parts":[[2026,4,1]]},"group-title":"Synthetic Biology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["R01HG012351"],"award-info":[{"award-number":["R01HG012351"]}]},{"name":"NIH","award":["R01CA310063"],"award-info":[{"award-number":["R01CA310063"]}]},{"name":"NIH","award":["R01NS131560"],"award-info":[{"award-number":["R01NS131560"]}]},{"name":"CIRM","award":["DISC4-19271"],"award-info":[{"award-number":["DISC4-19271"]}]},{"name":"DOD","award":["W81XWH-22-1-0401"],"award-info":[{"award-number":["W81XWH-22-1-0401"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Precise control over viral tropism remains a major challenge in the development of gene delivery technologies. We present MATCH (Modulation of AAV Tropism through Conjugation to Homing proteins), a modular biochemical method that enables programmable, receptor-guided retargeting of adeno-associated viruses (AAVs) through site-specific covalent protein conjugation. By incorporating a SpyTag peptide motif into selected AAV capsid loops, MATCH allows one-step, stoichiometrically defined attachment of recombinant SpyCatcher-linked targeting proteins to the viral surface. Using mosaic AAV-DJ and AAV9 capsids with controlled SpyTag incorporation, we achieve efficient assembly and tunable ligand display. MATCH-AAVs conjugated to an anti-CD3 single-chain antibody efficiently activate and transduce resting human T cells within mixed PBMC populations in vitro, achieving transduction levels of up to \u223c58% of total PBMCs. Conjugation to transferrin receptor (TfR1)-binding proteins yielded enhanced brain transduction in vivo, with murine TfR1-targeted MATCH-AAV9 exhibiting up to an 84-fold increase in brain expression relative to wild-type AAV9. Human TfR1-targeted vectors similarly enabled robust, receptor-dependent transduction both in vitro and in humanized mouse models. Both TfR-targeted vectors enabled widespread transduction of the parenchyma, consistent with TfR1-mediated crossing of the blood-brain barrier. Finally, we establish a streamlined one-pot \u201cMix-and-MATCH\u201d production strategy in which capsid and targeting ligands are co-expressed during vector generation, yielding functional, targeted AAVs at titers comparable to conventional production. This simple and generalizable synthetic-biology approach provides a versatile toolkit for rational AAV tropism engineering, offering a scalable route to custom vector design for research and therapeutic applications.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"715691v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.31.715691","type":"posted-content","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T11:10:24Z","timestamp":1775041824000},"source":"Crossref","is-referenced-by-count":0,"title":["Receptor-guided AAV Tropism Engineering via MATCH"],"prefix":"10.64898","author":[{"given":"Nolan","family":"Graham","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satheesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Rainaldi","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, CA USA"},{"name":"Biomedical Sciences Program, University of California San Diego, CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seoin","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of California San Diego, CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Portell","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Billy","family":"Santoso","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of California San Diego, CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3383-1287","authenticated-orcid":false,"given":"Prashant","family":"Mali","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026040314350819000_2026.03.31.715691v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-021-00017-7"},{"key":"2026040314350819000_2026.03.31.715691v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573"},{"key":"2026040314350819000_2026.03.31.715691v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.10.015"},{"key":"2026040314350819000_2026.03.31.715691v1.4","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2022.2060737"},{"key":"2026040314350819000_2026.03.31.715691v1.5","doi-asserted-by":"crossref","unstructured":"Ertl, H. 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