Abstract
Osteoarthritis (OA) is a common degenerative joint disease with limited disease-modifying therapies. Emerging evidence suggests that epigenetic dysregulation contributes to cartilage degeneration, but effective strategies to selectively target these pathways remain lacking. Here we show that the BRD4/Nav1.7 axis drives inflammatory and metabolic dysfunction in OA. Integrated single-cell and transcriptomic analyses identify BRD4 as a key regulator that enhances Nav1.7 transcription, promoting mitochondrial impairment and catabolic activation in chondrocytes. To therapeutically target this pathway, we develop a biomimetic hydrogel system incorporating chondrocyte membrane-coated nanoparticles for cartilage-specific delivery of a BRD4 proteolysis-targeting chimera (PROTAC), a molecule designed to induce selective protein degradation. This nanoplatform enables efficient intra-articular delivery, immune evasion and targeted retention in cartilage. Treatment suppresses inflammatory responses, restores mitochondrial function and reduces cartilage degeneration and pain behaviors in two mouse models of OA. These findings establish targeted BRD4 degradation as a disease-modifying strategy and provide a precision nanotherapeutic platform for OA.
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Data availability
The bulk RNA sequencing and single-cell RNA sequencing data generated in this study have been deposited in the NCBI Sequence Read Archive (SRA) under the BioProject accession number PRJNA1400711. Bulk RNA-seq data are available under the following SRA accession numbers: Control group: SRR36764747, SRR36764746, SRR36764741, SRR36764740, SRR36764739, SRR36764738; Case group: SRR36764737, SRR36764736, SRR36764735, SRR36764734, SRR36764745, SRR36764744. Single-cell RNA-seq data are available under the following SRA accession numbers: Control group: SRR36764743; Case group: SRR36764742. All other data supporting the findings of this study are available within the Article, Supplementary Information, or Source Data files. Source data are provided with this paper.
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Acknowledgements
This work was supported from Project of International Cooperation and Exchanges of the National Natural Science Foundation of China (No. 82020108017, D.C), 2025 Henan Provincial Medical Science and Technology Research Plan - Major Provincial-Ministerial Jointly FundedProject (SBGJ202501009, D.C.), China Postdoctoral Science Foundation under Grant Number(2025M781970, Q.Z.), Innovation Group Project of National Natural Science Foundation of China(No.81921002, D.C.), National Key Research and Development Program of China(No.2017FYA0205301, D.C.), Projects of Shanghai Science and Technology Commission (21DZ2203200,and No. 20142201300, D.C.), and Natural Science Foundation of Shanghai (No. 22ZR1467600, D.C.).
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Q.Z., T.X., Z.D., X.L., and Y.Z. contributed equally to this work. Q.Z., T.X., Z.D., X.L., and Y.Z. designed and performed the majority of experiments, analyzed the data, and drafted the manuscript. L.P., Z.G., W.W. (Weicheng Wang), and B.Z. were responsible for nanoparticle synthesis, hydrogel construction, and physicochemical characterization. Z.L., G.Y., H.Z., and Z.S. assisted with animal experiments and histological analyses. Q.L., J.L., Z.R., and Z.Y. performed bioinformatics analyses, including single-cell RNA sequencing and transcriptomic profiling. W.W. (Wei Wang) and Y.L. contributed to pain behavior assessment and imaging analysis. H.L. and J.M.F. provided critical technical support and conceptual advice. All authors discussed the results, critically revised the manuscript, and approved the final version.
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Zhao, Q., Xu, T., Du, Z. et al. Cartilage targeting hydrogel nanoplatform degrades BRD4 to alleviate osteoarthritis via Nav1.7 axis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71246-w
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DOI: https://doi.org/10.1038/s41467-026-71246-w
