Targeted and efficient AAV therapy for neuroblastoma via direct capsid-antibody coupling

Luoni, M.; Giannelli, S. G.; Parracino, S.; Morosi, F.; Ventura, E.; Di Pizio, A.; Muggeo, S.; Iannielli, A.; Canu, T.; Russo, T.; Antonio, E.; Pastorino, F.; Broccoli, V.

doi:10.1101/2025.11.12.687993

bioRxiv · 10.1101/2025.11.12.687993

Targeted and efficient AAV therapy for neuroblastoma via direct capsid-antibody coupling

Luoni, M.·Giannelli, S. G.·Parracino, S.·Morosi, F.·Ventura, E.·Di Pizio, A.·Muggeo, S.·Iannielli, A.·Canu, T.·Russo, T.·Antonio, E.·Pastorino, F.·Broccoli, V.

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Abstract

Adeno-associated viral (AAV) vectors are widely used in gene therapy for their versatility and safety, but their broad tropism limits cell-specific applications such as targeting primary or metastatic tumor cells. To address this, we developed AAV-STITCH, a strategy using SpyTag technology to covalently attach polypeptides to the AAV capsid. This allows precise, dose-dependent coupling of an anti-GD2 ScFv to a galactose-binding-deficient AAV9-W503A capsid, redirecting tropism specifically to GD2-expressing neuroblastoma (NB) cells. In pseudometastatic xenograft mouse models, AAV-STITCHGD2 selectively transduced NB tumor cells without transduction of healthy tissues. Furthermore, delivery of a suicide gene via AAV-STITCHGD2 suppressed tumor growth and extended survival in mice with subcutaneous and pseudometastatic NB xenografts. These findings establish the feasibility of engineering AAVs with cell-type-specific transduction properties, providing a powerful and adaptable platform for the selective elimination of NB tumor cells. This technology marks a meaningful advance toward next-generation, targeted cancer therapies with strong clinical potential.

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Luoni, M., Giannelli, S. G., Parracino, S., Morosi, F., Ventura, E., Di Pizio, A., Muggeo, S., Iannielli, A., Canu, T., Russo, T., Antonio, E., Pastorino, F., Broccoli, V.. 2025-11-13. Targeted and efficient AAV therapy for neuroblastoma via direct capsid-antibody coupling. https://doi.org/10.1101/2025.11.12.687993

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