Solving Mazes of Organelle‐Targeted Therapies with DNA Nanomachines

Despite decades of research, cancer remains a growing global health challenge. Nanomaterials-based therapeutics have shown promise, but their clinical applications are often limited by poor selectivity and undesirable side effects. Recently, deoxyribonucleic acid (DNA) based nanomachines have gained attention as intelligent drug carriers due to their ability to precisely target specific organelles. By leveraging rationally designed DNA nanomachines, it is possible to directly attack subcellular structures or deliver therapeutic agents to precise locations, triggering organelle-mediated cell death. This innovative approach offers several advantages, including enhanced efficacy, lower dosages, minimized off-target effects, reduced multidrug resistance, and improved therapeutic durability. This review explores the history and advancements of organelle-targeting strategies, providing new insights into targeting the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes using DNA nanomachines. The review also discusses the structures, design principles, and therapeutic mechanisms of these nanomachines, along with the integration of artificial intelligence-driven self-driving laboratories to enhance research growth, efficiency, and competitiveness. Finally, the current challenges, opportunities, and future directions in this evolving field are addressed, offering a roadmap for solving the intricate maze of organelle-targeted cancer therapies.