Injectable Matrix Metalloproteinase-Responsive Nanoparticle Hydrogel Scaffold for Sustained Local Drug Delivery in Fibrous Dysplasia
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ID: 315174
2026
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Abstract
Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibition has shown significant therapeutic benefit in fibrous dysplasia. However, sustained RANKL inhibition is required to maintain its therapeutic effect. Moreover, disease rebound following discontinuation of denosumab, a human monoclonal RANKL antibody, poses a major clinical challenge to fibrous dysplasia treatment, thereby highlighting the need for strategies that preserve lesion-level efficacy while limiting systemic exposure. Matrix metalloproteinases (MMPs), which are essential for osteoclast function and bone remodeling, have emerged as a key pathogenic pathway in fibrous dysplasia. Lesion profiling revealed elevated expression of MMP-9, -13, and -14 in osteoclast-rich fibrous dysplasia lesions, with dynamic regulation in response to pharmacologic RANKL inhibition and withdrawal. We hypothesized that matrix metalloproteinases may serve as lesion-associated biological cues for localized drug delivery in fibrous dysplasia. We developed an injectable, sustained, and matrix metalloproteinase-responsive local drug delivery system by integrating triglycerol monostearate nanoparticles within a dynamically crosslinked hyaluronic acid-based hydrogel scaffold (HPD/TGMS). To validate this strategy, the small-molecule RANKL inhibitor AS2676293 was loaded into triglycerol monostearate to generate HPD/TGMS@A. Matrix metalloproteinase-mediated cleavage of the ester linkage in triglycerol monostearate enabled protease-responsive drug release, further regulated by hydrogel-constrained perilesional retention. HPD/TGMS@A demonstrated favorable injectability, self-healing behavior, cytocompatibility, and matrix metalloproteinase-dependent anti-osteoclastic activity in vitro. HPD/TGMS@A significantly attenuated fibrous dysplasia lesion progression and improved bone microarchitecture in a GNASR201C knock-in fibrous dysplasia mouse model through perilesional injection. Altogether, these findings establish HPD/TGMS as a localized, lesion-responsive drug delivery strategy in fibrous dysplasia.
| Reference Key |
openalex_W7162693661
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| Authors | Lu Xing, Zhongyu Liu, Kaichao Wang, Xiaoqi Zhang, Jie Shen, Jing Shuai, Jiang Liu, Hongyun Zhao, Xianglong Han, Ding Bai, Qianming Chen, Xuefeng Zhao |
| Journal | journal of bone and mineral research : the official journal of the american society for bone and mineral research |
| Year | 2026 |
| DOI |
10.1093/jbmr/zjag091
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| URL | |
| Keywords | Keywords not found |
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