Macromolecular Design Principles for Polymer‐Lipid Hybrid Nanoparticles in RNA Delivery

The development of nonviral RNA delivery has been shaped by the chemistry of cationic materials and their capacity to organize nucleic acids through multivalent electrostatic interactions. Before ionizable lipid nanoparticle (LNP) formulations became central to clinically translated RNA therapeutics, nonviral nucleic acid delivery relied largely on cationic liposomes, cationic polymers, and polymer-lipid complexes that condensed anionic DNA or RNA into nanoscale assemblies. These systems established principles that continue to guide RNA nanomedicine, including electrostatic complexation, colloidal assembly, endosomal trafficking, charge-associated toxicity, degradable carrier design, and intracellular cargo release. Over the past decade, the clinical success of mRNA vaccines has consolidated small-molecule ionizable lipid LNPs as a major formulation platform, owing to their ability to combine efficient RNA encapsulation with improved tolerability, manufacturability, and in vivo expression. This Perspective revisits cationic polymer-lipid nanoparticles not as historical precursors to ionizable lipid LNPs, but as a macromolecular materials space that can clarify and extend current RNA delivery design. We discuss these systems within a structure-assembly-biointerface framework, emphasizing how polymer architecture, charge distribution, degradability, topology, and polymer-lipid interfacial organization govern RNA packaging, nanoparticle formation, intracellular release, tissue-selective interactions, and biological identity.