Biomimetic hybrid nanoparticles for dual regulation of macrophage pyroptosis and metabolism in rheumatoid arthritis

  • J Nanobiotechnology. 2026 May 8;24(1):652. doi: 10.1186/s12951-026-04502-2.
Guang Yang  #  1  2  3  4 ,  Lingxiao Xu  #  5  6  7  8 ,  Ruijie Zhang  #  1  2  3  4 ,  Zhenyu Zhu  9 ,  Kelei Wang  1  2  3  4 ,  Kaipeng Jin  1  2  3  4 ,  Yifan Wu  1  2  3  4 ,  Hanxu Huang  1  2  3  4 ,  Jiaxuan Zou  1  2  3  4 ,  Wushi Cui  1  2  3  4 ,  Xiaohua Yu  10  11  12  13 ,  Lingling Sun  14  15  16  17 ,  Zhenxuan Shao  18  19  20  21  22
Affiliations
  • 1. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 2. Orthopedics Research Institute of Zhejiang University, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 3. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 4. Clinical Research Center of Motor System Disease of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 5. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 6. Orthopedics Research Institute of Zhejiang University, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 7. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 8. Clinical Research Center of Motor System Disease of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 9. School of Public Health, Hangzhou Medical College, Hangzhou, 310053, China.
  • 10. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 11. Orthopedics Research Institute of Zhejiang University, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 12. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 13. Clinical Research Center of Motor System Disease of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 14. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 15. Orthopedics Research Institute of Zhejiang University, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 16. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 17. Clinical Research Center of Motor System Disease of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 18. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 19. Orthopedics Research Institute of Zhejiang University, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 20. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 21. Clinical Research Center of Motor System Disease of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 22. State Key Laboratory of Transvascular Implantation Devices, Hangzhou, 310009, China. [email protected].
  • # Contributed equally.
PMID: 42104436 DOI: 10.1186/s12951-026-04502-2
Abstract

Rheumatoid arthritis (RA), a chronic and debilitating autoimmune inflammatory disease, is critically driven by macrophages within the inflamed synovium. The inflammatory cascade is sustained by a synergistic imbalance between macrophage Pyroptosis and metabolic dysfunction, resulting in the formation of a dual barrier to effective intervention. GSDME-targeted siRNA delivery effectively blocks pyroptosis; however, uncorrected metabolic defects leave "saved" macrophages in a proinflammatory state, thereby aggravating RA. To address this "dual dilemma", folic acid-modified macrophage membrane-lipid hybrid nanoparticles (FA-MMLNPs) were engineered for spatiotemporally coordinated codelivery of GSDME siRNA (siG) and 4-octyl itaconate (4-OI). The biomimetic membrane promotes inflammatory homing, folic acid enhances FR-positive macrophage endocytosis, and the lipid core protects the siRNA and ensures synchronous release. Mechanistically, SiG inhibits Pyroptosis, whereas 4-OI restores Mitochondrial Metabolism to reprogram macrophages to an anti-inflammatory phenotype. This integrated material platform organically combines pathway-specific gene silencing, metabolic correction, and precise biointerface engineering, providing a versatile paradigm for material design in RA and Other inflammation-driven diseases.

Keywords
Biomimetic hybrid nanoparticles; Macrophage pyroptosis; Metabolic disorder; Rheumatoid arthritis; Targeted delivery.
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