Background <p>Oleanolic acid (OA), a pentacyclic triterpenoid abundantly present in various traditional Chinese herbs, exhibits promising anti-psoriatic potential owing to its broad pharmacological activities. Nevertheless, its clinical translation has been hindered by challenges including poor aqueous solubility, limited cutaneous permeation, and rapid systemic clearance, all of which compromise bioavailability when administered topically. To address these limitations, we designed and developed encapsulated and disulfide bonded OA-hyaluronic acid nanoprodrugs (OA-NPs@OA) for topical treatment of psoriasis in this study.</p> Results <p>OA-NPs@OA exhibited significantly enhanced cellular uptake <i>via</i> CD44 receptor-mediated endocytosis in keratinocytes, achieving a markedly lower IC₅₀ value compared to free OA and considerably stronger apoptosis induction effects. In the IMQ-induced murine model, topically applied OA-NPs@OA demonstrated superior transdermal penetration with sustained lesional retention, effectively reversing psoriatic phenotypes with remarkably reduced PASI scores and splenomegaly, normalized epidermal thickness, and suppressed immune inflammation and cytokines. OA-NPs@OA exhibited superior effects to free OA and Calcipotriol Ointment. Mechanistically, OA-NPs@OA concurrently suppressed keratinocyte hyperproliferation <i>via</i> blocking the YAP-AREG pathway axis and reduced immune cell infiltration by downregulating chemokine networks, breaking the psoriatic inflammatory loop. Crucially, OA-NPs@OA showed excellent biosafety with no dermal or systemic toxicity following consecutively topical administration.</p> Conclusions <p>OA-NPs@OA represents a novel targeted nanotherapy that overcomes the limitations of OA in anti-psoriasis by offering enhanced bioavailability, multimodal anti-psoriatic action, and optimized safety profiles.</p> Graphical Abstract <p></p>