Calcium Phosphate Nanoparticle‐Immobilized Macrophage‐Derived Extracellular Vesicle Nanohybrid Facilitates Diabetic Bone Regeneration

Abstract Diabetes significantly hinders bone regeneration, and existing tissue engineering therapies struggle to improve the hyperglycemia‐induced inflammatory microenvironment, resulting in unbalanced bone remodeling. M2‐macrophage‐derived extracellular vesicles (M2EVs) possess inherent immunomodulatory properties and promote stem cell differentiation; however, their therapeutic potential in diabetic bone regeneration is significantly limited by poor stability and insufficient osteoinductive capacity. Inspired by biomineralization, a calcium phosphate nanoparticle‐immobilized macrophage‐derived small extracellular vesicle nanohybrid (M2EV@CaP) is developed by in situ growth of inorganic nanocrystals on M2EV surfaces. In the nanohybrid system, the chemically inert CaP‐nanoparticle‐reinforced shell provides structural protection for M2EV, inhibiting vesicle aggregation caused by membrane protein denaturation/cross‐linking or lipid phase transition through physical barrier. More importantly, M2EV@CaP provides bioavailable calcium/phosphorus ion reservoirs and signaling molecules for bone regeneration and releases responsively under inflammation‐induced acidic conditions. In vitro, M2EV@CaP significantly enhances macrophage polarization toward a reparative M2 phenotype, and promotes stem cell osteogenic differentiation under high‐glucose inflammatory conditions by activating the Ca 2+ –Akt signaling axis. In vivo, hydrogel‐assisted delivery of M2EV@CaP significantly promotes bone regeneration in diabetic rat calvarial defects through immunomodulation and osteoinduction. This study proposes a nanohybridization strategy based on inorganic nanoparticles reinforcing biostructures, offering a promising extracellular vesicle therapy for complex pathological conditions.