负载siOASL的载细胞颗粒通过多种机制抑制中性粒细胞胞外陷阱的过度积累，从而缓解系统性红斑狼疮的进展

Abstract

Elevated serum expression of OASL is correlated with the progression of systemic lupus erythematosus. • Exosomes derived from Cargo-siOASL facilitate the differentiation of naive CD4 + T cells into regulatory T cells. • Apoptotic products generated by Cargo-siOASL enhance the efficiency of macrophage-mediated clearance of neutrophil extracellular traps. • Cargo-siOASL effectively mitigates the progression of systemic lupus erythematosus in murine models. Recent studies have revealed a critical role of neutrophil extracellular traps (NETs) in systemic lupus erythematosus (SLE) progression. Therapies utilizing mesenchymal stem cells (MSCs) have shown considerable potential in managing immune-related diseases. Notably, the recently developed denucleated MSCs, termed cargocytes, not only substantially improve the delivery efficiency and persistence of therapeutic molecules—thereby enhancing treatment efficacy—but also exhibit erythrocyte-like apoptotic characteristics in vivo , contributing to overall treatment safety. Cargocytes therefore represent an ideal therapeutic carrier. The present study initially established a significant correlation between SLE progression and the elevated expression of oligodeoxynucleotidyl synthetase-like protein (OASL). Subsequent in vitro experiments further demonstrated that OASL overexpression markedly inhibits the differentiation of regulatory T cells (Tregs). Based on these findings, we engineered cargocytes loaded with an siRNA specifically targeting OASL (Cargo-siOASL). Experimental results indicated that Cargo-siOASL administration markedly enhanced Treg differentiation in MRL/lpr mice, thereby suppressing NET formation. Moreover, the erythrocyte-like apoptotic products induced by Cargo-siOASL increased the phagocytic capacity of macrophages, thereby accelerating NET clearance and substantially alleviating renal damage. In summary, this study presents a novel therapeutic strategy that mitigates excessive immune activation ass