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Nanoparticle-Loaded Injectable Hydrogel Alleviates Titanium Particle-Induced Osteolysis by Disrupting
Sipeng Lin1,2,3, Taihe Liu2, Qi Zhu1
1Department of Orthopedics, Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanwei, Guangdong 516621, P. R. China.
Biomaterials Research
|April 20, 2026
Summary
Researchers identified the GATA6/DDX3X axis regulating inflammation from joint implant wear particles. A novel hydrogel therapy targeting DDX3X (DEAD-box helicase 3 X-linked) reduced inflammation and bone loss in preclinical models.
Area of Science:
- Biomaterials Science
- Immunology
- Orthopedic Surgery
Background:
- Aseptic loosening (AL) is the primary cause of joint arthroplasty failure, driven by macrophage inflammation in response to prosthetic wear particles.
- The interplay between endoplasmic reticulum and mitochondrial stress exacerbates this inflammation, but key regulators are not fully understood.
Purpose of the Study:
- To investigate the GATA6/DDX3X axis in titanium particle (TiP)-induced macrophage inflammation.
- To explore the therapeutic potential of nanoparticle-loaded injectable hydrogels for AL.
Main Methods:
- Fabrication and characterization of si-DDX3X-loaded nanoparticle hydrogels (si-DDX3X NPs@Hy).
- In vivo evaluation of therapeutic efficacy in a mouse model of TiP-induced osteolysis.
- Analysis of macrophage inflammatory responses, including DDX3X expression, inflammasome activation, and cytokine secretion.
Main Results:
- DDX3X expression was upregulated in TiP-stimulated macrophages and tissues from AL patients.
- DDX3X promoted endoplasmic reticulum-mitochondrial crosstalk, NLRP3 inflammasome assembly, and IL-1β secretion.
- GATA6 suppressed DDX3X transcription, mitigating inflammatory effects.
- si-DDX3X NPs@Hy treatment reduced osteolysis, osteoclastogenesis, and M1 macrophage polarization in mice.
Conclusions:
- The GATA6/DDX3X axis is a critical regulator of TiP-driven macrophage inflammation.
- si-DDX3X NPs@Hy represents a promising therapeutic strategy for wear particle-induced inflammation in joint arthroplasty.
- This approach has potential to improve the long-term success of joint replacement surgery.
