Engineering Metal Nanomaterials for Precision Genetic Medicine

ABSTRACT Genetic medicine has established a transformative paradigm for precision therapy. To date, most advances have relied on viral vectors and non‐viral lipidic and polymeric nanocarriers. Although metal nanomaterials have not achieved clinical approval for gene therapy, recent progress in precise synthesis and versatile functionalization has made them promising candidates, together with their unique physicochemical characteristics and intrinsic theranostic properties. This review first summarizes recent advances in the most widely studied metal nanomaterials, gold nanoparticles, for delivery of diverse genetic cargoes through covalent conjugation and electrostatic assembly, emphasizing the rational design of hybrid nanoplatforms for stimuli‐responsive release and synergistic gene therapy effects. Distinctive internalization mechanisms and key physicochemical properties governing therapeutic efficacy are also discussed. Subsequently, emerging ultrasmall metal nanoclusters are highlighted, which can be engineered at the atomic level and exhibit unique in vivo performance, including efficient renal clearance, intrinsic luminescence, theranostic capability, and gene therapy efficacy. Other metal‐based platforms, such as metal–organic frameworks and iron oxide nanoparticles, are also covered. Finally, key challenges and future opportunities for engineering metal nanomaterials in genetic medicine are identified, with particular emphasis on the role of artificial intelligence and modular design in overcoming manufacturing scalability and regulatory barriers to clinical translation.