αFAP-specific nanobodies mediate a highly precise retargeting of modified AAV2 capsids thereby enabling specific transduction of tumor tissues

Due to the refractiveness of tumor tissues to adeno-associated virus (AAV) transduction, AAV vectors are poorly explored for cancer therapy delivery. Here, we aimed to engineer AAVs to target tumors by enabling the specific engagement of fibroblast activation protein (FAP). FAP is a cell surface receptor distinctly upregulated in the reactive tumor stroma, but rarely expressed in healthy tissues. Thus, targeting FAP presents an opportunity to selectively transduce tumor tissues. To achieve this, we modified the capsid surface of AAV2 with an αFAP nanobody to retarget the capsid to engage FAP receptor. Following transduction, we observed a 23- to 80-fold increase in the selective transduction of FAP