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Background <p>Renal ischemia–reperfusion injury (IRI) is a major complication following nephron-sparing surgery, with limited preventive strategies. Annexin A2 (ANXA2) is upregulated after renal IRI, but its functional role and therapeutic potential remain unclear.</p> Methods <p>Utilizing ANXA2 knockout (KO) and wild-type mice subjected to renal IRI, we assessed injury, fibrosis, and cell death pathways. In vitro studies employed mouse renal tubular epithelial cells (TECs) with ANXA2 or charged multivesicular body protein (CHMP) 2A knockdown or overexpression. Molecular mechanisms were investigated via co-immunoprecipitation, mass spectrometry, and immunofluorescence. The Kidney-Targeting Peptide (KTP)-conjugated, ANXA2-loaded lipid nanoparticle (KTP-LNP@ANXA2) was synthesized and characterized. Its efficacy was evaluated in vitro and in a mouse renal IRI model.</p> Results <p>ANXA2 was significantly upregulated post-IRI, predominantly in the renal medulla. KO mice exhibited exacerbated medullary injury, increased fibrosis, and enhanced necroptosis, as indicated by elevated phosphorylated MLKL (p‑MLKL) levels and severe apical membrane disruption, whereas no genotype‑dependent differences were detected in the selected markers of apoptosis, pyroptosis, or ferroptosis at 24&#xa0;h. ANXA2 deficiency amplified the inflammatory response, increasing neutrophil infiltration through the upregulation of C-X-C motif chemokine ligand (CXCL) 1 and CXCL2. Mechanistically, ANXA2 associated with CHMP2A, a component of the endosomal sorting complex required for transport (ESCRT)-III membrane repair complex, following IRI, promoting ESCRT-III assembly at the apical membrane to counteract necroptosis. Knocking down CHMP2A abolished the protective effect of ANXA2. The engineered KTP-LNP@ANXA2 demonstrated excellent stability, biocompatibility, and enhanced uptake by renal TECs. Pre-treatment with KTP-LNP@ANXA2 in mice effectively delivered ANXA2 to the kidneys, attenuated IRI severity, reduced necroptosis and inflammation, and diminished neutrophil recruitment.</p> Conclusion <p>ANXA2 confers protection against renal IRI by interacting with CHMP2A to facilitate ESCRT-III-mediated inhibition of TEC necroptosis, thereby attenuating subsequent inflammation. Enhancement of renal ANXA2 levels via engineered LNPs represents a novel and promising therapeutic strategy for preventing renal IRI.</p> Graphical abstract <p></p>

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Kidney‑enriched lipid nanoparticles delivering ANXA2 alleviate renal ischemia–reperfusion injury via CHMP2A-mediated necroptosis inhibition

  • 期刊论文

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  • 发表日期：

    2026年7月18日

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  • Dong Lai,
  • Qing Bi,
  • Jichen Wang,
  • Weihao Chen,
  • Shouqing Cao,
  • Huaikang Li,
  • Hao Gong,
  • Shangwei Li,
  • Xu Zhang,
  • Huayi Feng,
  • Xiubin Li,
  • Junnan Xu

摘要

Background

Renal ischemia–reperfusion injury (IRI) is a major complication following nephron-sparing surgery, with limited preventive strategies. Annexin A2 (ANXA2) is upregulated after renal IRI, but its functional role and therapeutic potential remain unclear.

Methods

Utilizing ANXA2 knockout (KO) and wild-type mice subjected to renal IRI, we assessed injury, fibrosis, and cell death pathways. In vitro studies employed mouse renal tubular epithelial cells (TECs) with ANXA2 or charged multivesicular body protein (CHMP) 2A knockdown or overexpression. Molecular mechanisms were investigated via co-immunoprecipitation, mass spectrometry, and immunofluorescence. The Kidney-Targeting Peptide (KTP)-conjugated, ANXA2-loaded lipid nanoparticle (KTP-LNP@ANXA2) was synthesized and characterized. Its efficacy was evaluated in vitro and in a mouse renal IRI model.

Results

ANXA2 was significantly upregulated post-IRI, predominantly in the renal medulla. KO mice exhibited exacerbated medullary injury, increased fibrosis, and enhanced necroptosis, as indicated by elevated phosphorylated MLKL (p‑MLKL) levels and severe apical membrane disruption, whereas no genotype‑dependent differences were detected in the selected markers of apoptosis, pyroptosis, or ferroptosis at 24 h. ANXA2 deficiency amplified the inflammatory response, increasing neutrophil infiltration through the upregulation of C-X-C motif chemokine ligand (CXCL) 1 and CXCL2. Mechanistically, ANXA2 associated with CHMP2A, a component of the endosomal sorting complex required for transport (ESCRT)-III membrane repair complex, following IRI, promoting ESCRT-III assembly at the apical membrane to counteract necroptosis. Knocking down CHMP2A abolished the protective effect of ANXA2. The engineered KTP-LNP@ANXA2 demonstrated excellent stability, biocompatibility, and enhanced uptake by renal TECs. Pre-treatment with KTP-LNP@ANXA2 in mice effectively delivered ANXA2 to the kidneys, attenuated IRI severity, reduced necroptosis and inflammation, and diminished neutrophil recruitment.

Conclusion

ANXA2 confers protection against renal IRI by interacting with CHMP2A to facilitate ESCRT-III-mediated inhibition of TEC necroptosis, thereby attenuating subsequent inflammation. Enhancement of renal ANXA2 levels via engineered LNPs represents a novel and promising therapeutic strategy for preventing renal IRI.

Graphical abstract