Hu Ruizhi, Qin Junchang, Feng Wei, Song Xinran, Huang Hui, Dai Chen, Zhang Bo, Chen Yu
Department of Ultrasound, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P. R. China.
Department of Ultrasound, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China.
Sci Adv. 2025 Jun 27;11(26):eadu3919. doi: 10.1126/sciadv.adu3919. Epub 2025 Jun 25.
Macrophage pyroptosis has been identified as a critical pathological mechanism in inflammation-related atherosclerosis (AS). In this work, we have demonstrated that Zn features the strongest anti-inflammatory performance by screening 10 representative metal ions, and the MTC1 agonists can trigger lysosomal Zn 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.
巨噬细胞焦亡已被确定为炎症相关动脉粥样硬化（AS）的关键病理机制。在本研究中，我们通过筛选10种代表性金属离子证明锌具有最强的抗炎性能，且MTC1激动剂可触发溶酶体锌释放并抑制巨噬细胞焦亡。基于这些发现，我们进一步构建了一种与黏脂素瞬时受体电位通道1（MTC1）相关的治疗性纳米平台，用于内源性触发溶酶体锌释放以抑制炎症并阻断巨噬细胞焦亡。该纳米平台由介孔二氧化硅纳米颗粒组成，用于递送MTC1激动剂和碳纳米点，它们可通过清除毒性活性氧、抑制巨噬细胞焦亡、调节巨噬细胞转变以及重建动脉粥样硬化免疫微环境来协同发挥抗动脉粥样硬化作用。这些发现表明，通过利用自溶酶体锌库可有效阻断巨噬细胞焦亡，这为管理其他炎症性疾病提供了涉及溶酶体锌调节的纳米治疗范例。
