Microneedle-based delivery of cell membrane vesicles as IL-17RA decoys for Psoriasis treatment.

The dysregulation of IL-17/IL-17 receptor A (IL-17RA) signaling axis is a central driver of multiple autoimmune diseases. In contrast to targeting individual IL-17 cytokines, blocking IL-17RA simultaneously inhibits the receptor engagement of multiple IL-17 ligands, thereby effectively suppressing downstream pathway activation. Brodalumab, the only approved IL-17RA-blocking antibody, suggests robust clinical efficacy. However, its inhibition of IL-17RA has been associated with an increase in systemic IL-17 C levels, which is related to suicidal ideation and behavior. Consequently, the development of novel strategies capable of broadly blocking IL-17 signaling remains critically important. This study developed a novel therapeutic strategy by engineering cell-membrane vesicles with IL-17RA (IL-17RA-CMVs) as high-avidity decoy receptors for effectively blocking the IL-17/IL-17 receptor A (IL-17RA) signaling axis. Stable 293T cell lines exhibiting high surface expression of mouse or human IL-17RA (m/hIL-17RA), mediated by a platelet-derived growth factor receptor (PDGFR) transmembrane domain, were successfully constructed and applied for the preparation of m/hIL-17RA-CMVs. The mIL-17RA-CMVs were efficiently loaded into hyaluronic acid-based microneedles (mIL-17RA-CMVs-MNs), and the resulting mIL-17RA-CMVs-MNs exhibited sufficient mechanical strength to penetrate the skin and rapidly dissolved within 5 min upon insertion. In an imiquimod (IMQ)-induced murine psoriasis model, the topical application of mIL-17RA-CMVs-MNs significantly alleviated disease severity, as evidenced by a remarkable reduction in Psoriasis Area and Severity Index (PASI) scores, suppression of epidermal hyperplasia, and normalization of spleen index. Mechanistic studies revealed that the treatment mIL-17RA-CMVs-MNs markedly downregulated the expression of key IL-17RA pathway-related inflammatory mediators (CXCL1, CXCL2, CCL20) and antimicrobial peptides (S100A7/A8/A9) in skin lesions. Furthermore, in vitro experiments indicated that hIL-17RA-CMVs effectively functioned as decoy receptors, neutralizing IL-17 A and consequently inhibiting the upregulation of pro-inflammatory cytokines and hyperproliferation in HaCaT keratinocytes. This study presents a pioneering approach that synergizes the broad-spectrum neutralization capability of engineered decoy receptor vesicles with the localized and minimally invasive delivery advantage of microneedles. These findings position IL-17RA-CMVs (or IL-17RA-CMVs-MNs) as a highly promising and translatable therapeutic modality for the treatment of psoriasis and potentially other IL-17-mediated inflammatory diseases.