Payload‐Driven Design of Polymeric Carriers for Nucleic Acid Delivery: Insights from Structure–Function Relationships

Polymeric carriers provide versatile platforms for nucleic acid delivery. This review introduces a novel perspective inspired by protein structural organization to explore structure–function relationships of polymeric carriers, highlighting requirements of different nucleic acid payloads. By bridging fundamental concepts with practical design strategies, a framework is provided to move beyond trial‐and‐error toward payload‐specific design, guiding next‐generation polymeric carriers for therapeutic applications. Abstract Polymeric carriers are gaining increasing attention for the delivery of a range of clinically relevant nucleic acid (NA) payloads, due to their efficacy, safety, and modular chemistry. While the requirements for an “optimal” carrier depend strongly on the NA payload, research has largely centered on carrier properties rather than the unique needs of the payload. Therefore, in this review, a novel perspective inspired by protein structural organization is introduced to explore structure–function relationships of polymeric carrier systems, highlighting the diverse requirements of different NA payloads. To gain deeper mechanistic insights, the complicated polymer/NA delivery systems are deconvoluted into four hierarchical levels, including molecular composition, structural features, complexation, and 3D integration. In addition to outlining recent experimental strategies, it is emphasized that the structural diversity and tunability of polymer chemistry provide a foundation for payload‐specific carrier design. Critical advances are expected in the molecular design of polymeric carriers to enhance NA delivery efficiency, improve biological safety and incorporate multifunctionality, particularly compared to lipid‐based platforms that are currently ahead in clinical applications. A payload‐specific design framework may guide development of next‐generation polymeric carrier systems for basic research, biotechnology, and therapeutic applications. Polymeric carriers provide versatile platforms for nucleic acid delivery. This review introduces a novel perspective inspired by protein structural organization to explore structure–function relationships of polymeric carriers, highlighting requirements of different nucleic acid payloads. By bridging fundamental concepts with practical design strategies, a framework is provided to move beyond trial-and-error toward payload-specific design, guiding next-generation polymeric carriers for therapeutic applications. Abstract Polymeric carriers are gaining increasing attention for the delivery of a range of clinically relevant nucleic acid (NA) payloads, due to their efficacy, safety, and modular chemistry. While the requirements for an “optimal” carrier depend strongly on the NA payload, research has largely centered on carrier properties rather than the unique needs of the payload. Therefore, in this review, a novel perspective inspired by protein structural organization is introduced to explore structure–function relationships of polymeric carrier systems, highlighting the diverse requirements of different NA payloads. To gain deeper mechanistic insights, the complicated polymer/NA delivery systems are deconvoluted into four hierarchical levels, including molecular composition, structural features, complexation, and 3D integration. In addition to outlining recent experimental strategies, it is emphasized that the structural diversity and tunability of polymer chemistry provide a foundation for payload-specific carrier design. Critical advances are expected in the molecular design of polymeric carriers to enhance NA delivery efficiency, improve biological safety and incorporate multifunctionality, particularly compared to lipid-based platforms that are currently ahead in clinical applications. A payload-specific design framework may guide development of next-generation polymeric carrier systems for basic research, biotechnology, and therapeutic applications. Advanced Science, EarlyView.