Therapeutic reprogramming of circulating myeloid cells via signal regulatory protein α extracellular vesicles in acute kidney injury.

Abstract

Acute kidney injury (AKI) presents significant clinical challenges, with high mortality and progression risk to chronic kidney disease. Mechanisms remain incompletely understood and disease-specific therapies are lacking. Recent evidence highlights the pivotal role of infiltrating myeloid cells in perpetuating kidney inflammation. CD47, a key cell surface immune checkpoint protein, is upregulated in inflammation and regulates myeloid cell infiltration, making it an attractive therapeutic target. Single-cell RNA sequencing and CD47 protein staining were used to identify CD47 expressions in human AKI specimens and two mouse models (cis-platin and bilateral ischemia/reperfusion). To therapeutically exploit this, we engineered extracellular vesicles (EVs) from human bone marrow mesenchymal stem cells to express a high-affinity signal regulatory protein a (SIRPα) variant (SIRP-EVs), the ligand for CD47. The efficacy of SIRP-EVs was evaluated in murine AKI models. CD47 expression was significantly elevated in myeloid populations, particularly macrophages, in both human AKI tissues and mouse models. A single systemic administration of SIRP-EVs in murine AKI models exhibited therapeutic effects, including improved kidney function markers, reduced pro-inflammatory cytokine production, and ameliorated kidney histopathology. Mechanistically, SIRP-EVs preferentially localize to circulating myeloid cells, modulate CD47 expression, and subsequently inhibit their migration into injured kidney tissue. Moreover, single cell transcriptomics revealed that SIRP-EV treatment reprograms circulating macrophages toward pro-resolving phenotypes, characterized by upregulation of genes associated with tissue repair. Targeting CD47 on circulating myeloid cells with SIRP-EVs provides a systemic, blood-focused immunomodulatory strategy that precedes tissue infiltration, contrasting with conventional tissue-centric approaches. Our findings support SIRP-EVs as a promising therapeutic option for AKI and potentially other inflammation-driven diseases through selective modulation and reprogramming of peripheral myeloid cells.