Metabolism-based artificial organelles: From precise construction to smart theranostics

Cellular metabolic dysregulation is a core driver of major diseases, including cancer, neurodegenerative disorders, and cardiovascular conditions. However, conventional interventions such as small-molecule drugs and gene editing are hampered by off-target effects, delivery challenges, and a lack of spatiotemporal precision, resulting in a failure to effectively reengineer pathological metabolic networks. Artificial organelles, constructed via a "bottom-up" bioinspired approach, represent a paradigm shift from systemic intervention to "metabolic system reconstruction," offering a revolutionary strategy to precisely mimic, repair, or augment specific metabolic functions at the subcellular level. Here, we systematically review recent advances in metabolism-based artificial organelles, from their precise construction to smart theranostic applications. We first elaborate on the core construction strategies, including lipid and protein self-assembly, microfluidics, 3D bioprinting and biomembrane fusion for enabling dynamic interactions and content delivery, followed by a dissection of the design principles for modulating three metabolic pillars: (1) remodeling energy metabolism by mimicking mitochondrial function and regulating glycolysis; (2) controlling biosynthesis by emulating the endoplasmic reticulum (ER) and substance transport networks; and (3) reshaping redox homeostasis by mimicking peroxisomes through multienzyme cascades and intelligent responsive systems that precisely regulate signaling molecules such as reactive oxygen species (ROS). We link these functional designs to specific metabolic vulnerabilities in diseases and showcase applications in neurodegenerative disorders, cancer, cardiovascular diseases, and inflammatory conditions. Specific strategies include repairing damaged neurons through synergistic energy supplementation and antioxidation or inhibiting tumors via a combination of "starvation therapy" and pro-oxidative "gas therapy." Finally, we critically address the key challenges in biocompatibility, systemic complexity, in vivo delivery, and clinical translation and outline future perspectives toward intelligent, autonomous systems integrated with artificial intelligence (AI)-driven design and multiscale, "artificial tissue" constructs. This review aims to provide a theoretical framework and technological roadmap for designing the next generation of smart metabolic intervention tools. Scheme. Artificial organelles (AOs) represent a paradigm shift from systemic intervention to 'metabolic system reconstruction' for treating diseases driven by metabolic dysregulation. This review presents a comprehensive framework spanning bottom-up construction strategies (self-assembly to 3D bioprinting), functional designs targeting three metabolic pillars (energy metabolism, biosynthesis, redox homeostasis), and precision therapeutic applications in cancer, neurodegeneration, and inflammatory diseases. We critically analyze translational challenges including biocompatibility, scalability, and in vivo delivery, while proposing future directions toward AI-driven intelligent systems. This work provides a roadmap for engineering next-generation metabolic intervention tools.