Dexamethasone-Integrated Mesenchymal Stem Cells for Systemic Lupus Erythematosus Treatment <i>via</i> Multiple Immunomodulatory Mechanisms.

Abstract

The therapeutic application of mesenchymal stem cells (MSCs) has good potential as a treatment strategy for systemic lupus erythematosus (SLE), but traditional MSC therapy still has limitations in effectively modulating immune cells. Herein, we present a promising strategy based on dexamethasone liposome-integrated MSCs (Dexlip-MSCs) for treating SLE <i>via</i> multiple immunomodulatory pathways. This therapeutic strategy prolonged the circulation time of dexamethasone liposomes <i>in vivo</i>, restrained CD4⁺T-cell proliferation, and inhibited the release of proinflammatory mediators (IFN-γ and TNF-α) by CD4⁺T cells. In addition, Dexlip-MSCs initiated cellular reprogramming by activating the glucocorticoid receptor (GR) signaling pathway to upregulate the expression of anti-inflammatory factors such as cysteine-rich secretory protein LCCL-containing domain 2 (CRISPLD2) and downregulate the expression of proinflammatory factors. In addition, Dexlip-MSCs synergistically increased the anti-inflammatory inhibitory effect of CD4⁺T cells through the release of dexamethasone liposomes or Dex-integrated MSC-derived exosomes (Dex-MSC-EXOs). Based on these synergistic biological effects, we demonstrated that Dexlip-MSCs alleviated disease progression in MRL/lpr mice more effectively than Dexlip or MSCs alone. These features indicate that our stem cell delivery strategy is a promising therapeutic approach for clinical SLE treatment.