A C‐Nucleoside Analogue of Cordycepin With High Metabolic Stability and Potent Anti‐Psoriatic Activity via Microneedle Delivery

Psoriasis is a chronic inflammatory disorder characterized by immune dysregulation and epidermal hyperplasia. Cordycepin, a natural adenosine analogue from traditional Chinese medicine Cordyceps militaris, possesses broad anti‑inflammatory and immunomodulatory properties, but its poor metabolic stability limits clinical use. Herein, 22 cordycepin derivatives for anti-psoriasis were designed and synthesized. Among them, CPD3a, featuring a stable C─C glycosidic bond, exhibited potent anti‑inflammatory activity, high metabolic stability, and high resistance to in vivo metabolic deamination. CPD3a was formulated into a microneedle array (CPD3a-MN) for the topical treatment of psoriasis. In a psoriasis-like mouse model, CPD3a-MN exhibited potent, dose-dependent efficacy, significantly reducing pathological symptoms, ameliorating epidermal hyperplasia, and suppressing systemic inflammation. Meanwhile, CPD3a-MN rebalanced systemic immunity by suppressing splenic neutrophils and inflammatory dendritic cells while increasing regulatory T cells and M2 macrophages. Activation of adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway and a marked antioxidant effect were also observed following CPD3a-MN treatment. Transcriptomic analysis demonstrated that CPD3a-MN modulated the psoriatic transcriptome, suppressing interleukin-17 (IL-17)/nuclear factor-kappa B (NF-κB)-driven inflammatory networks and concurrently activating genes involved in keratinocyte differentiation and epidermal barrier restoration. Moreover, CPD3a-MN was well‑tolerated, with good biocompatibility. Collectively, CPD3a represents a superior therapeutic alternative to cordycepin for topical psoriasis treatment.