2. Academic Validation
  3. Calcium Phosphate Nanoparticle-Immobilized Macrophage-Derived Extracellular Vesicle Nanohybrid Facilitates Diabetic Bone Regeneration

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

  • Adv Mater. 2025 Oct 1:e09410. doi: 10.1002/adma.202509410.
Xiaolan Wu 1,  Shanshan Jin 1,  Qibo Wang 1,  Liyuan Chen 1,  Xinjia Cai 1,  Min Yu 1,  Houzuo Guo 1,  He Zhang 1,  Hangbo Liu 1,  Chang Li 1,  Shiying Zhang 1,  Xinmeng Shi 1,  Lifang Feng 1,  Shiqiang Gong 2,  Dan Luo 3,  Cunyu Wang 4,  Yan Liu 1 4
Affiliations

Affiliations

  • 1 Department of Orthodontics, Peking University School and Hospital for Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, 100081, China.
  • 2 Center of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences, Beijing, 101400, China.
  • 4 Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing, 100091, China.
PMID: 41030201 DOI: 10.1002/adma.202509410
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 CA2+-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.

Keywords

biomimetic mineralization; diabetic bone defect; extracellular vesicle nanoparticles; functional modification; tissue engineering.

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