biostudies-literatureUnknownCheema Y<h4>Purpose –</h4>The extracellular matrix (ECM) is a major component of the tissue microenvironment which may pose a barrier to the distribution of AAV in target organs, preventing delivery of therapeutic cargo. We sought to address this potential barrier to AAV gene therapy by furthering our understanding of AAV-ECM interactions. We hypothesized that both the AAV serotype and ECM composition will impact AAV transport and gene delivery.<h4>Methods–</h4>AAV2, AAV6, and AAV8 viral vectors were fluorescently labeled to allow for visualization of their diffusion through the ECM. Lung, liver, and small intestinal submucosal dECM hydrogels were formulated as models of the ECM with tissue-specific biomolecular content. We then characterized AAV and nanoparticle diffusion within decellularized ECbioRxiv : the preprint server for biology2025.08.01.668133https://www.ebi.ac.uk/biostudies/studies/S-EPMC12324481biostudies-literatureBarrier Function of the Extracellular Matrix in AAV Gene Therapy.PMC12324481Cheema YCahn DDuncan GAWolf MKumar SfalseBarrier Function of the Extracellular Matrix in AAV Gene Therapy.<h4>Purpose –</h4>The extracellular matrix (ECM) is a major component of the tissue microenvironment which may pose a barrier to the distribution of AAV in target organs, preventing delivery of therapeutic cargo. We sought to address this potential barrier to AAV gene therapy by furthering our understanding of AAV-ECM interactions. We hypothesized that both the AAV serotype and ECM composition will impact AAV transport and gene delivery.<h4>Methods–</h4>AAV2, AAV6, and AAV8 viral vectors were fluorescently labeled to allow for visualization of their diffusion through the ECM. Lung, liver, and small intestinal submucosal dECM hydrogels were formulated as models of the ECM with tissue-specific biomolecular content. We then characterized AAV and nanoparticle diffusion within decellularized EC2025-01-01T00:00:00Z2025 Aug2026-04-29T03:17:10.96Z2026-04-29T03:07:34.592ZS-EPMC123244814076651510.1101/2025.08.01.668133