In January 2026, the team led by Huang Wei, Zhao Chen and Lei Yiting from the First Affiliated Hospital of Chongqing Medical University, in collaboration with the team of João F. Mano from the University of Aveiro, published a review article in Research entitled "Metabolism-Regulating Microspheres: Design Principles, Therapeutic Applications Across Multisystem Diseases, and Future Perspectives".

Background of the Integration of Metabolism and Microspheres
Contemporary understanding of the pathogenesis of chronic diseases has undergone a fundamental shift: metabolic dysregulation has evolved from a correlative phenomenon to a widely recognized causal driver. As a core regulator, aberrant metabolic activity can initiate and sustain complex pathological cascades. Traditional pharmacological approaches, which mainly intervene in metabolism via systemic administration, exhibit significant limitations including poor tissue specificity, off-target effects, and dose-limiting toxicities. Therefore, the development of innovative strategies capable of precisely correcting tissue-specific metabolic disorders while maintaining systemic metabolic homeostasis has become a critical challenge.

Against this background, engineered microspheres have evolved from traditional passive sustained-release carriers into transformative platforms capable of actively regulating local metabolism. By integrating chemical signal guidance and physical structural modulation, these microspheres construct intelligent systems that can "reprogram" pathological metabolic networks in a spatiotemporally specific manner, providing a novel avenue for achieving precise therapy transitioning from "symptom management" to "etiological intervention" .

Characteristics and Preparation Methods of Microspheres
The efficacy of metabolism-regulating microspheres is rooted in the synergistic design and precise control of their physicochemical properties. Chemical design aims to encode metabolic instructions by loading and releasing ionic signals (e.g., Mg²⁺, Sr²⁺), metabolic substrates (e.g., α-ketoglutarate), or pathway modulators (e.g., antioxidant nanozymes) to directly intervene in intracellular energy and anabolic pathways. Physical design modulates cell behavior through mechanical and structural signals by tuning the stiffness and elasticity, microstructure and porosity, as well as size distribution of microspheres. For instance, stiff microspheres promote osteogenic differentiation, whereas soft microspheres can suppress tumor metabolism.
The key to realizing these designs lies in advanced fabrication techniques: microfluidics enables monodispersity and complex core–shell structures; electrospraying facilitates the mild encapsulation of bioactive molecules; emulsification is suitable for large-scale production; and photolithography allows precise engineering of geometric features and surface topology. The selection and integration of these methods form the foundation for microspheres to function as "metabolic instruction systems".

Applications of Metabolic Microspheres in Orthopedics
In orthopedics, metabolism-regulating microspheres are driving a paradigm shift from "passive support" to "active metabolic intervention". For osteoarthritis, microspheres implanted into the joint cavity act as "intelligent regulators". For example, microspheres containing cerium oxide nanozymes can continuously scavenge reactive oxygen species and restore mitochondrial function, thereby shifting chondrocyte metabolism from a pro-inflammatory catabolic state to an anabolic homeostatic state.

For osteoporosis, microspheres with bone-targeting and sustained-release designs (e.g., loading strontium ions or calcitonin) continuously regulate the local bone microenvironment, activating osteoblasts to promote bone formation and inhibiting osteoclast activity to reduce bone resorption, thereby systemically correcting imbalanced bone metabolism.

In the repair of large bone defects, microspheres act as a "spatiotemporal metabolic command system". They regulate metabolic polarization of macrophages by releasing metal ions, provide metabolic substrates to overcome local "energy crises", or deliver youthful extracellular matrix signals to rejuvenate aged stem cells, thereby promoting vascularized bone regeneration through multi-dimensional synergy.

Challenges and Future Perspectives of Metabolic Microspheres
Despite great promise, the clinical translation of metabolism-regulating microspheres still faces severe challenges. The primary obstacle is inefficient tissue-specific delivery. In bone, for instance, the dense mineralized matrix, compartmentalized vascular network, and mechanical stress derived from physiological loading severely limit the penetration, uniform distribution, and controlled release of microspheres. Second, individual metabolic heterogeneity—marked by distinct metabolic profiles among patients and even across different disease stages—makes "one-size-fits-all" microsphere formulations unable to achieve consistent therapeutic outcomes. Finally, the complexity of metabolic networks and long-term safety remain concerns. Intervention targeting a single pathway may trigger compensatory adaptation or systemic metabolic shifts, and long-term biocompatibility and distant effects remain unclear.

Future directions focus on addressing these challenges through interdisciplinary innovation: developing personalized microspheres based on metabolomic analysis of patient body fluids; utilizing artificial intelligence-driven design to integrate multi-omics data for optimizing formulations and predicting in vivo behavior; and adopting human-relevant validation platforms such as organ chips and organoids to systematically evaluate the metabolic regulatory efficacy and safety of microspheres in biomimetic environments, thereby accelerating their reliable translation into clinical applications.