The effective clinical translation of messenger RNA (mRNA), small interfering RNA (siRNA), and microRNA (miRNA) for therapeutic purposes hinges on the development of efficient delivery systems. Key challenges include their susceptibility to degradation, limited cellular uptake, and inefficient intracellular release. Polymeric drug conjugates (PDCs) offer a promising solution, combining the benefits of polymeric carriers and therapeutic agents for targeted delivery and treatment. This comprehensive review explores the clinical translation of nucleic acid therapeutics, focusing on polymeric drug conjugates. It investigates how these conjugates address delivery obstacles, enhance systemic circulation, reduce immunogenicity, and provide controlled release, improving safety profiles. The review delves into the conjugation strategies, preparation methods, and various classes of PDCs, as well as strategic design, highlighting their role in nucleic acid delivery. Applications of PDCs in treating diseases such as cancer, immune disorders, and fibrosis are also discussed. Despite significant advancements, challenges in clinical adoption persist. The review concludes with insights into future directions for this transformative technology, underscoring the potential of PDCs to advance nucleic acid-based therapies and combat infectious diseases significantly.