Fine-tuned phenylboronic acid polymer assembly with tannic acid enables adeno-associated virus to evade and suppress neutralizing antibody responses

Adeno-associated virus (AAV) has emerged as a promising vector for gene therapy; however, its therapeutic efficacy is often limited by pre-existing and treatment-induced neutralizing antibodies (NAbs). To address this challenge, we developed an AAV-loaded ternary complex through the sequential assembly of AAV, tannic acid (TA), and phenylboronic acid (PBA)-modified block copolymers, protecting AAV from NAbs by polymer shielding. In this study, we systematically investigated the structural parameters of PBA-modified block copolymers and their impact on NAb evasion and immune responses. We found that the optimized polymer chain lengths of each segment enhanced NAb evasion efficacy in vitro and in vivo by increasing steric hindrance and complex stability while preserving AAV transduction efficiency through intracellular pH-responsive release. Furthermore, the optimized AAV ternary complexes achieved suppression of de novo NAb production by more than 50% compared with AAV alone following administration. These findings highlight the importance of polymer structure in balancing immune evasion and transduction and demonstrate that the structurally tuned AAV9 ternary complexes represent a promising strategy to broaden the clinical applicability of AAV-based gene therapy to seropositive patients. • Neutralizing antibodies (NAbs) significantly limit AAV-based gene delivery. • AAV9-loaded ternary complexes, formed by sequential assembly of AAV9, TA, and PBA-block copolymers, sterically shield AAV9 from NAbs. • Fine-tuned copolymer structures improve NAb evasion via increased steric hindrance and complex stability. • Optimized copolymer structures markedly suppress de novo immunogenicity of AAV9 ternary complexes. • Structural tuning of polymers expands AAV-based gene therapy to seropositive patients.