To overcome this problem of vector inefficiency, we design a novel gene delivery strategy, in which HAdV5-PUMA was ‘piggybacked’ on a baculovirus vector carrying CAR on its envelope14, resulting in the efficient cell entry of the vector BVCARHAdV5-PUMA into the FLS. We demonstrate in this study that PUMA gene transfer into FLS by BVCARHAdV5-PUMA results in rapid and extensive cell death by PUMA-induced apoptosis. The pro-apoptotic effect is not substantially reduced in the presence of proinflammatory cytokines, which mimic the environment of inflamed joints. Using the adjuvant-induced arthritis (AIA) rat model, we find that a single intra-articular injection of BVCARHAdV5-PUMA significantly decreases joint inflammation, and improves joint function with reduced joint damage and bone loss. The results of this study show that the intra-articular administration of a PUMA-expressing vector has therapeutic potential as a treatment for various forms of arthritis in which FLS proliferation is implicated.