2. Academic Validation
  3. Lysosomal zinc nanomodulation blocks macrophage pyroptosis for counteracting atherosclerosis progression

Lysosomal zinc nanomodulation blocks macrophage pyroptosis for counteracting atherosclerosis progression

  • Sci Adv. 2025 Jun 27;11(26):eadu3919. doi: 10.1126/sciadv.adu3919.
Ruizhi Hu 1,  Junchang Qin 2,  Wei Feng 3,  Xinran Song 3,  Hui Huang 3,  Chen Dai 1,  Bo Zhang 1 4,  Yu Chen 3 5 6
Affiliations

Affiliations

  • 1 Department of Ultrasound, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P. R. China.
  • 2 Department of Ultrasound, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China.
  • 3 Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai 200444, P. R. China.
  • 4 State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, P. R. China.
  • 5 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou 325000, P. R. China.
  • 6 Shanghai Institute of Materdicine, Shanghai 200051, P. R. China.
PMID: 40561010 DOI: 10.1126/sciadv.adu3919
Abstract

Macrophage Pyroptosis has been identified as a critical pathological mechanism in inflammation-related atherosclerosis (AS). In this work, we have demonstrated that Zn2+ features the strongest anti-inflammatory performance by screening 10 representative metal ions, and the MTC1 agonists can trigger lysosomal Zn2+ release and inhibit Pyroptosis in macrophages. Based on these findings, we further engineered a mucolipin TRP Channel 1 (MTC1)-related therapeutic nanoplatform for endogenously triggering lysosomal zinc release to curb inflammation and block macrophage Pyroptosis. This nanoplatform consists of mesoporous silica nanoparticles to deliver MTC1 agonists and carbon nanodots, which could synergistically exert antiatherosclerotic effect by scavenging toxic Reactive Oxygen Species, inhibiting macrophage Pyroptosis, modulating macrophage transition, and rebuilding atherosclerotic immune microenvironment. These findings demonstrate that macrophage Pyroptosis can be efficiently blocked via leveraging self-lysosomal zinc pool, which provides the paradigm of lysosomal zinc modulation-involved nanotherapeutics for managing Other inflammatory diseases.

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