Holistic regulation of the diabetic osteo-microenvironment via NIR-II nanocarriers with dual NO/pH responsiveness for enhanced bone regeneration

Xudong Xie; Junli Yang; Chong Ding; Yiming Li; Fawwaz Ai-Smadi; Kangkang Zha; Chuanlu Lin; Ze Lin; Chenyan Yu; Ruiyin Zeng; Weixian Hu; Jiewen Liao; lizhi Ouyang; Tian Xia; Peng Zhao; Bobin Mi; Guohui Liu

doi:10.1016/j.bioactmat.2025.07.025

Bioactive Materials (Nov 2025)

Holistic regulation of the diabetic osteo-microenvironment via NIR-II nanocarriers with dual NO/pH responsiveness for enhanced bone regeneration

Xudong Xie,
Junli Yang,
Chong Ding,
Yiming Li,
Fawwaz Ai-Smadi,
Kangkang Zha,
Chuanlu Lin,
Ze Lin,
Chenyan Yu,
Ruiyin Zeng,
Weixian Hu,
Jiewen Liao,
lizhi Ouyang,
Tian Xia,
Peng Zhao,
Bobin Mi,
Guohui Liu

Affiliations

Xudong Xie: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
Junli Yang: Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, PR China
Chong Ding: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
Yiming Li: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
Fawwaz Ai-Smadi: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
Kangkang Zha: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
Chuanlu Lin: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
Ze Lin: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
Chenyan Yu: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
Ruiyin Zeng: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
Weixian Hu: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
Jiewen Liao: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
lizhi Ouyang: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China
Tian Xia: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Corresponding author.
Peng Zhao: Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, PR China; Corresponding authors.
Bobin Mi: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China; Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research (Huazhong University of Science and Technology), Wuhan, Hubei 430022, PR China; Corresponding author. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China.
Guohui Liu: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, PR China; Corresponding authors. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China.

DOI: https://doi.org/10.1016/j.bioactmat.2025.07.025
Journal volume & issue: Vol. 53
pp. 754 – 772

Abstract

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Diabetic conditions impair bone regeneration due to dysregulated macrophage polarization and inflammatory imbalance. Current therapies often fail to address systemic immune homeostasis. Herein, a bone-targeted nanoplatform (abbreviated as AgSr-MSNs) is engineered to scavenge excess nitric oxide (NO) and respond to the acidic diabetic microenvironment based on upregulated inducible nitric oxide synthase (iNOS) expression in M1 macrophages residing within both the diabetic bone marrow and localized osteolytic regions in our study. The system integrates silver sulfide quantum dots (Ag2S QDs) and Sr2+ into mesoporous silica nanoparticles (MSNs), encapsulated with rhodamine/β-cyclodextrin and surface-modified with alendronate for bone-specific targeting. Under near-infrared (NIR) irradiation, the nanoparticles induce macrophage repolarization toward M2 phenotypes through JAK/STAT signaling pathway, followed by upregulating anti-inflammatory mediators (TGF-β, PD-L1) and tissue-regenerative factors (BMP-2/4, VEGF-B), while suppressing pro-inflammatory cytokines (CCR2, S100A4). This dual NO/pH-responsive platform synergistically mitigates inflammatory dysregulation, enhances osteogenesis, and promotes angiogenesis. In diabetic models, systemic administration with NIR-mediated mild hyperthermia reduces CD86+ macrophages and TNF-α levels while elevating CD206+ macrophages locally and systemically. Concurrently, it boosts CD31, Runx2, and osteocalcin (OCN) expression levels at defect sites, indicating restored vascularization and osteogenesis. This strategy addresses the pathological triad of diabetic osteopathy—chronic inflammation, vascular insufficiency, and osteogenic impairment—providing a translatable nanotherapeutic paradigm for metabolic bone disorders.

Published in Bioactive Materials

ISSN: 2452-199X (Online)
Publisher: KeAi Communications Co., Ltd.
Country of publisher: China
LCC subjects: Technology: Electrical engineering. Electronics. Nuclear engineering: Materials of engineering and construction. Mechanics of materials; Science: Biology (General)
Website: https://www.keaipublishing.com/en/journals/bioactive-materials/

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