Microfluidics-engineered mannitol- stabilized solid lipid nanoparticle hydrogel for enhanced topical delivery of apremilast in psoriasis therapy

Abstract

• Microfluidic AJM enable homogeneous LNPs powder production. • Novel APR@Mann-LNP produce dual-targets for psoriasis therapy. • Mannitol-functionalization enhance LNP lyoprotection and antipruritics effects. • APR@Mann-LNP hydrogel boost skin embedding for sustained APR delivery. • APR@Mann-LNP hydrogel enhance localized IMQ induced psoriasis therapy. Psoriasis, a chronic inflammatory skin disease, highlights the need for effective topical therapies to circumvent the systemic limitations of oral agents, such as apremilast (APR), a PDE4 inhibitor. Herein, a novel single-step microfluidic platform is reported for the continuous and reproducible production of monodisperse APR-loaded LNP(APR@Mann-LNPs) using mannitol as a stabilizer. This method achieves high drug loading (>85%) and uniform particle distribution, whereas mannitol serves a dual role as both a nanoparticle stabilizer and targeting psoriatic neurogenic inflammation. In vitro, the formulation demonstrated sustained pH-responsive drug release, enhanced cellular uptake, and proapoptotic activity in HaCaT cells. In an imiquimod-induced murine psoriasiform model, the APR@Mann-LNP hydrogel significantly ameliorated clinical PASI scores, reversed pathological epidermal hyperplasia, and attenuated splenomegaly. Mechanistically, it suppressed key pro-inflammatory cytokines (IL-17A, IL-23, TNF-α, and IL-1β), which was attributed to enhanced skin penetration, sustained release, and the combined pharmacological action of APR and mannitol. This mannitol-stabilized nano platform improves the topical APR bioavailability and safety, directly aligning with first-line treatment paradigms in psoriasis therapy. This study presents a novel microfluidic platform for the continuous production of mannitol-stabilized LNP engineered for topical psoriasis therapy. In an imiquimod-induced mouse model, the APR@Mann-LNP hydrogel significantly suppressed clinical severity, normalized epidermal hyperplasia, downregulated key inflammatory cytokines (IL-17, IL-23, and TNF-α), and attenuated systemic inflammation. This nanoplatform offers a targeted, stable, and enhanced topical strategy for psoriasis management.