Metabolism-Regulating Microspheres: Design Principles, Therapeutic Applications Across Multisystem Diseases, and Future Perspectives.

Metabolism-regulating microspheres have evolved from conventional drug carriers into active platforms capable of spatiotemporally reprogramming pathological metabolic networks. Chronic diseases are increasingly understood to be driven by metabolic dysregulation, highlighting the need for therapeutic strategies that enable localized and precise metabolic intervention. This review systematically outlines the core design principles of these microspheres, emphasizing the synergistic integration of engineered chemical properties, such as ionic signaling, metabolite delivery, and pathway modulator release, with tailored physical characteristics, including stiffness, porosity, and size of the microspheres. Together, these features construct "metabolic instruction systems" that correct dysregulated pathways at the tissue level. Their versatile applications include orthopedic diseases, such as osteoporosis, osteoarthritis, and bone defects; ophthalmic conditions, including glaucoma and diabetic retinopathy; and gynecological disorders, such as premature ovarian insufficiency, ovarian cancer, and endometriosis. These systems target key metabolic abnormalities, such as glycolytic dysregulation, mitochondrial dysfunction, and oxidative stress, which are recognized as central drivers of disease pathogenesis across multiple organ systems. Despite considerable progress, clinical translation remains limited by tissue-specific delivery barriers, interindividual metabolic heterogeneity, and long-term safety concerns within dynamic metabolic networks. Emerging strategies, such as personalized formulations, artificial-intelligence-driven designs, and organ-on-a-chip validation platforms, are being developed to address these challenges. With ongoing interdisciplinary innovation, metabolism-regulating microspheres hold great promise as precise therapeutic modalities for a spectrum of chronic diseases rooted in metabolic imbalance, offering targeted and sustained metabolic correction.