J Adv Res. 2026 Jul 25. pii: S2090-1232(26)00592-8. [Epub ahead of print]
Xunshan Ren,
Huangming Zhuang,
Junming Zhu,
Hongbao Jiang,
Jinxuan Zhang,
Yuelong Zhang,
Rongling Feng,
Rui Shi,
Ruijun Zhang,
Le Li,
Miradj Siddick Adam,
Panghu Zhou.
INTRODUCTION: An increase in the number of senescent cells with advancing age is a major predisposing factor for aging-related osteoarthritis (OA). However, effective intervention strategies targeting cellular senescence have yet to be developed. Increasing evidence suggests that rising epigenetic entropy, specifically the detachment of heterochromatin from the nuclear envelope, is a driver of cellular senescence.
OBJECTIVES: We sought to engineer an in situ structural restoration strategy that re-anchors unstable heterochromatin to the nuclear lamina of cells using bioorthogonal click chemistry.
METHODS: We developed a bioorthogonal reaction-driven chromatin architecture restoration system (BR-CARS) using azide-modified anti-LMNB1 and DBCO-conjugated anti-H3K9me3 antibodies. To enable cytosolic delivery, we established a freeze-thaw-facilitated liposomal encapsulation strategy. Crucially, the high molecular weight of these antibodies prevents them from crossing intact nuclear pore complexes of healthy cells, ensuring specificity for senescent cells in which the nuclear barrier is compromised. Efficacy and selectivity were evaluated in senescent chondrocytes and a rat OA model using confocal 3D reconstruction and multi-omics analyses.
RESULTS: Our results confirmed that in vivo, BR-CARS was predominantly delivered to the superficial and upper-middle zones of the articular cartilage, where it preferentially infiltrated senescent chondrocyte nuclei compared with those of healthy controls. Upon nuclear entry, the components underwent a click reaction, tethering heterochromatin to the nuclear lamina. This forced approximation compacted the chromatin structure. Integrated ATAC-seq and RNA-seq analyses revealed that this structural restoration reduced chromatin accessibility at senescence-associated gene loci and repetitive elements, silencing their expression.
CONCLUSIONS: This study pioneers an anti-senescence strategy based on structural epigenetic engineering that not only mechanically reverses cellular senescence but also achieves intrinsic selectivity by leveraging the biophysical defects of the senescent nucleus. This nuclear envelope pretargeting strategy emerges as a precise and safe preclinical candidate for OA treatment, with translational potential extending to a wider spectrum of age-associated pathologies.
Keywords: Chondrocyte; Heterochromatin; Osteoarthritis; Senescence