Suppression of senescent metabolism of adipose tissue by rebalancing mitochondrial homeostasis via a selective drug delivery system

  • J Nanobiotechnology. 2026 Jun 2. doi: 10.1186/s12951-026-04594-w.
Liwei Wang  #  1  2  3  4  5  6 ,  Kaicheng Xu  #  1  2  3 ,  Ziye Guo  #  1  2  3 ,  Xiaoyong Wu  #  1  2  3 ,  Di Wang  1  2  3 ,  Liang Chen  1  2  3 ,  Donghua Huang  1  2  3 ,  Kaile Wu  1  2  3 ,  Yubin Zhao  1  2  3 ,  Minjun Yao  1  2  3 ,  Liming Zheng  1  2  3 ,  Xiaobo Yang  1  2  3 ,  Chenyi Ye  1  2  3 ,  Wushi Cui  1  2  3 ,  Wanli Li  7  8  9 ,  An Liu  10  11  12 ,  Mao Zhang  13  14  15 ,  Jianbin Xu  16  17  18
Affiliations
  • 1. Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, P. R. China.
  • 2. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, 310009, P. R. China.
  • 3. Orthopedics Research Institute of Zhejiang University, Hangzhou, 310009, P. R. China.
  • 4. Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 5. Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Hangzhou, 310009, China.
  • 6. Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou, 310009, China.
  • 7. Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, P. R. China. [email protected].
  • 8. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, 310009, P. R. China. [email protected].
  • 9. Orthopedics Research Institute of Zhejiang University, Hangzhou, 310009, P. R. China. [email protected].
  • 10. Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, P. R. China. [email protected].
  • 11. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, 310009, P. R. China. [email protected].
  • 12. Orthopedics Research Institute of Zhejiang University, Hangzhou, 310009, P. R. China. [email protected].
  • 13. Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China. [email protected].
  • 14. Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Hangzhou, 310009, China. [email protected].
  • 15. Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou, 310009, China. [email protected].
  • 16. Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, P. R. China. [email protected].
  • 17. Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, 310009, P. R. China. [email protected].
  • 18. Orthopedics Research Institute of Zhejiang University, Hangzhou, 310009, P. R. China. [email protected].
  • # Contributed equally.
PMID: 42231423 DOI: 10.1186/s12951-026-04594-w
Abstract

Background: Aging is characterized by a progressive decline in physiological function. Among various organs, adipose tissues play an important regulator of systemic metabolism and energy homeostasis. Age-associated alterations in adipose tissue are closely linked to organismal aging. Targeting senescent adipose tissue has therefore emerged as a potential strategy for mitigating age-related dysfunction. The purpose of this study was to develop and evaluate a selective drug delivery system for Anti-aging therapy.

Results: We report a targeted anti-ageing platform based on extracellular vesicles functionalized with the P3 peptide, enabling efficient delivery of dasatinib and quercetin to aged adipose tissue. This platform effectively inhibits senescence-associated secretory phenotype (SASP) in both aged adipocytes and adipose explants in vitro, concomitant with restoration of specific adipocyte function. Furthermore, systemic administration in aged mice contributes to improved physical performance and basal metabolic capacity, alongside attenuation of adipose tissue senescence. Mechanistically, these effects are probably mediated by drug-induced activation of Mitophagy and the consequent reprogramming of cellular energy metabolism.

Conclusion: These findings underscore the pivotal role of adipose tissue in systemic aging processes. The developed delivery platform effectively targets senescent adipose tissue, suppresses SASP, restores physiological function, and enhances organismal physical performance. This work proposes a conceptual framework linking aging and metabolism, offering a promising strategy for organ- or tissue-specific Anti-aging interventions.

Keywords
Adipose tissue; Extracellular vesicles; Motor performance; Senescence-associated secretory phenotype.
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