Demand for gene therapies capable of treating previously inaccessible targets has risen precipitously in the past decade. Adeno-associated viruses (AAVs) are the preferred vector for gene delivery because of their favorable safety profile and tissue tropism, but they have significant manufacturing challenges, with end-to-end yields as low as 10-30%. To combat these low yields, we developed IsoTagAAV, a novel purification technology for AAV that is a departure from the chromatographic paradigm in downstream processing. This proprietary technology uses a self-scaffolding recombinant protein reagent that can improve manufacturing yields. It enables purification by cost-effective and scalable filtration processes and improves product quality with minimal optimization. Herein, we describe the development of IsoTagAAV, provide a head-to-head comparison to industry-leading affinity chromatography (evaluation carried out through a joint research project with Capsida Biotherapeutics), and demonstrate how it can reduce cost of goods for a clinical AAV program by 25%.