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

ABSTRACT

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.