Sequence-defined polymers for predictable gene delivery

Polymer-mediated gene delivery is evolving from stochastic design methodologies to precise molecular engineering. Traditional polymers, although effective in nucleic acid complexation, face challenges in terms of structural heterogeneity, unpredictable pharmacokinetics and inefficient endosomal escape. These challenges have driven interest in sequence-defined polymeric systems, which enable atomic-level control over monomer composition, charge distribution and functionality. Sequence-defined polymers provide opportunities to establish robust structure-function relationships, overcome biological barriers and achieve targeted delivery to specific tissues. This Review examines the architectural evolution of polymeric gene carriers and highlights how increasing structural precision correlates with enhanced functional performance. Synthetic methodologies enabling sequence control are analysed, from solid-phase approaches to flow chemistry and supramolecular templating. By integrating polymer science with biological outcomes, we present a strategic framework for addressing persistent challenges in non-viral gene delivery.