Abstract <p>PTEs, or polythioesters, are a new and exciting family of biodegradable polymers that provide exceptional adaptability for tailored drug delivery systems. PTEs are distinguished by having thioester linkages in their backbone and are very sensitive to intracellular stimuli like increased glutathione levels and enzymatic activity. Their distinct chemical structure enables regulated drug release and site-specific breakdown, which makes them perfect transporters for proteins, peptides, nucleic acids, and chemotherapeutics. The chemistry, synthesis methods, and degradation mechanisms of PTEs are thoroughly reviewed in this paper, emphasizing the design flexibility and tunability of these materials. The paper also looks at how PTEs are designed to react to enzymatic and redox stimuli, and how these characteristics are used in platforms that respond to one or more stimuli. A thorough discussion of drug loading and release processes is provided, with a focus on the variables affecting the effectiveness of intracellular delivery. PTEs’ biocompatibility, pharmacokinetics, and safety characteristics are severely assessed, as are their recent uses in gene-based therapies, peptide and protein delivery, and cancer treatment. Furthermore, PTEs perform better in stimuli-sensitive and precision-targeted treatments when compared to conventional polymers like polyesters, polyanhydrides, and polycarbonates. Even with their preclinical success, there are still issues with long-term safety, regulatory processes, and clinical translation. Future directions, such as hybrid PTE systems, AI-driven design, and their incorporation into customized treatment, are outlined in the review’s conclusion. All things considered, PTEs mark a paradigm change in smart polymer-based therapies by providing fresh chances for efficient and responsive medication distribution.</p> Graphical Abstract <p></p>