Polymeric Delivery of DNA‐Encoded Biologics

ABSTRACT This Perspective provides an overview of the fundamental concepts regarding polymeric delivery of DNA‐encoded biologics for the durable expression of biologics such as monoclonal antibodies (mAbs), endogenous proteins, and peptides. The concept of vectorizing proteins from the delivery of engineered plasmid DNA (pDNA) has long been considered to treat a range of infectious diseases, oncology, metabolic, and autoimmune disorders. However, viral vectors are non‐redosable and often immunogenic, and lipid nanoparticles face challenges associated with stability, burst release, and toxicity. By contract, polymer nanoparticles (PNPs) with ionizable amine moieties can readily self‐assemble with encoding pDNA and deliver high doses of cargo. We describe this concept within the rapid growth of therapeutic mAbs as a clinical modality. Specifically, PNP design considerations are outlined using conventional principles from gene therapy, protein engineering, and controlled drug delivery. This convergent approach, which we are pursuing with data‐driven materials discovery and an Artificial Intelligence (AI) enabled platform, creates promising new classes of potent biologics to be developed at scale. The breadth of possible programmable proteins from encoded DNA ranges from specialized mAbs that treat HIV to important anti‐obesity peptides, representing exciting avenues for polymer scientists to make important contributions to the next generation of genetic medicines.