Programmable Assembly of Adeno-Associated Virus-Antibody Composites for Receptor-Mediated Gene Delivery

Alina C. Zdechlik, Yungui He, Eric J. Aird, Wendy R. Gordon, Daniel Schmidt

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Adeno-associated virus (AAV) has emerged as a viral gene delivery vector that is safe in humans, able to infect both dividing and arrested cells and drive long-term expression (>6 months). Unfortunately, the naturally evolved properties of many AAV serotypes-including low cell type specificity and largely overlapping tropism- A re mismatched to applications that require cell type-specific infection, such as neural circuit mapping or precision gene therapy. A variety of approaches to redirect AAV tropism exist, but there is still the need for a universal solution for directing AAV tropism toward user-defined cellular receptors that does not require extensive case-by-case optimization and works with readily available components. Here, we report AAV engineering approaches that enable programmable receptor-mediated gene delivery. First, we genetically encode small targeting scaffolds into a variable region of an AAV capsid and show that this redirects tropism toward the receptor recognized by these targeting scaffolds and also renders this AAV variant resistant to neutralizing antibodies present in nonhuman primate serum. We then simplify retargeting of tropism by engineering the same variable loop to encode a HUH tag, which forms a covalent bond to single-stranded DNA oligos conjugated to store-bought antibodies. We demonstrate that retargeting this HUH-AAVs toward different receptors is as simple as "arming" a premade noninfective AAV template with a different antibody in a conjugation process that uses widely available reagents and requires no optimization or extensive purification. Composite antibody-AAV nanoparticles structurally separate tropism and payload encapsulation, allowing each to be engineered independently.

Original languageEnglish (US)
Pages (from-to)1093-1106
Number of pages14
JournalBioconjugate Chemistry
Issue number4
StatePublished - Apr 15 2020

Bibliographical note

Funding Information:
A.Z. and D.S. designed the study. E.J.A. and W.R.G advised on HUH technology. A.Z. conducted the experiments with Y.H.’s assistance. A.Z. and D.S. analyzed the data and authored the manuscript. All authors have given approval to the final version of the manuscript. This study was supported by an NIH NIMH U01 MH109038 grant to D.S. and an NIH NIGMS R35 GM119483 grant to W.R.G. A.Z. and E.J.A. received salary support from a Biotechnology Training Grant NIH T32GM008347. The authors declare no competing financial interest.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


Dive into the research topics of 'Programmable Assembly of Adeno-Associated Virus-Antibody Composites for Receptor-Mediated Gene Delivery'. Together they form a unique fingerprint.

Cite this