2. Academic Validation
  3. Acid neutralization and metal-phenolic nanomedicine on-demand release microspheres for reversing cartilage degeneration

Acid neutralization and metal-phenolic nanomedicine on-demand release microspheres for reversing cartilage degeneration

  • J Control Release. 2025 Dec 13:390:114523. doi: 10.1016/j.jconrel.2025.114523.
Sixiang Wang 1,  Yan Gao 2,  Lili Dong 3,  Jinsong Shu 2,  Fan Feng 4,  Long Ren 5,  Xiaorong Hu 6,  Li Yang 5,  Mingxing Lei 2,  Xi Chen 5,  Lianhong Pan 7,  Xueqiang Wang 8,  Kang Xu 9,  Chunli Wang 10
Affiliations

Affiliations

  • 1 Ningbo Rehabilitation Hospital, Wenzhou Medical University, Ningbo, Zhejiang 315040, China; Department of Rehabilitation Medicine, The Second Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
  • 2 National Innovation and Attracting Talents "111" base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
  • 3 Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China.
  • 4 Hubei Shizhen Laboratory, Wuhan 430065, China; School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China.
  • 5 Department of Rehabilitation Medicine, The Second Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
  • 6 Ningbo Rehabilitation Hospital, Wenzhou Medical University, Ningbo, Zhejiang 315040, China.
  • 7 Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing 400030, China. Electronic address: [email protected].
  • 8 Department of Rehabilitation Medicine, The Second Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China. Electronic address: [email protected].
  • 9 Hubei Shizhen Laboratory, Wuhan 430065, China; School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China. Electronic address: [email protected].
  • 10 Hubei Shizhen Laboratory, Wuhan 430065, China; School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, China. Electronic address: [email protected].
PMID: 41397492 DOI: 10.1016/j.jconrel.2025.114523
Abstract

Osteoarthritis (OA) is a degenerative joint disorder characterized by complex network dysregulation across the entire joint, which significantly compromises the efficacy of single-target therapeutic interventions. Pathological acidosis and magnesium ion (Mg2+) deficiency have been mechanistically associated with cartilage matrix degradation, abnormal subchondral bone remodeling, and chronic inflammation, collectively driving OA progression. In this study, we engineered porous PLGA microspheres (Cur-Mg/PLGA MPs) incorporating curcumin-modified magnesium hydroxide nanosheets to effectively neutralize excessive hydrogen ions and sustained the release of Mg-Cur nanocomplexes through microporous structures. This acid responsive and neutralization delivery system enhanced the therapeutic capacity of metal-phenolic nanomedicine in suppressing inflammatory responses, inhibiting osteoclast differentiation, and reducing chondrocyte catabolic activity, thereby achieving optimal cartilage preservation. Our in vitro experiments revealed that Cur-Mg/PLGA MPs exhibit remarkable chondroprotective effects under both inflammatory and acidic microenvironmental conditions. Moreover, in vivo evaluations demonstrated that this microsphere system can significantly alleviate OA-associated pain, effectively suppress osteoclast activation, and substantially maintain cartilage matrix homeostasis. Mechanistic investigations identified that Cur-Mg/PLGA MPs inhibit macrophage-to-osteoclast differentiation through ACOD1-mediated mitochondrial metabolic rewiring, ultimately disrupting the "acidosis-osteolysis "vicious cycle in OA pathogenesis. These findings present a novel comprehensive therapeutic strategy for OA management, which has demonstrated significant efficacy in rat models and hold promising potential for clinical translation.

Keywords

Acid neutralization; Metal–phenolic nanomedicine; Mitochondrial metabolic rewiring; Osteoarthritis; Osteoclast differentiation; Subchondral bone resorption.

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