Self‐Assembled <i>Dictamni Cortex</i> Nanoparticles Ameliorate Psoriasis by Epigenetic Modulation of HSP90AB1 and Suppression of the Inflammatory Response

Psoriasis, a chronic immune-mediated dermatological disease with high recurrence rates and limited therapeutic efficacy, requires novel treatment strategies. Dictamni Cortex (BXP), a traditional Chinese medicine (TCM), has demonstrated potential in alleviating psoriasis; however, its clinical application is hampered by poor water solubility and low bioavailability. It is developed infinite coordination polymer nanoparticles (BXP-Fe (III) ICPs, NB), which enhance the aqueous solubility by 95-fold and bioavailability of BXP, exerting therapeutic effect through efficient transdermal delivery. NB significantly suppresses keratinocyte hyperproliferation, inflammation, and oxidative stress in both M5 (a cocktail of cytokines)-treated human epidermal keratinocytes (HEKa) cells and imiquimod (IMQ)-induced psoriatic mice. Nascent proteomics identified heat shock protein 90 alpha family class B member 1 (HSP90AB1) as a key target downregulated by NB. It is further revealed that NB suppresses HSP90AB1 transcription by inhibiting its activator, CCCTC-binding factor (CTCF), and disrupts the HSP90AB1-CDC37 (cell division cycle 37, the co-chaperone) chaperone complex, thereby inactivating the pivotal client proteins STAT3 and Akt. Notably, NB demonstrated superior therapeutic efficacy over the canonical HSP90 inhibitor AUY922. This study highlights NB as a promising topical nanotherapy for psoriasis, integrating TCM with modern nanotechnology to overcome pharmacological limitations. The underlying molecular mechanisms of NB are elucidated through the CTCF-HSP90AB1-STAT3 axis.