Microfluidics engineered methotrexate-loaded cRGD lipid-based nanoparticles for the selective targeting and inhibition of αvβ3 integrin to provide dual mechanistic targeting of psoriasis

Psoriasis is a chronic inflammatory skin condition with limited therapeutic options. Among the available options, methotrexate (MTX) is a systemic agent used to manage moderate-to-severe psoriasis. However, its frequent clinical use is limited by its dose-limiting toxicity, necessitating innovative strategies to enhance its targeting, efficacy, and safety. Here, we present a novel microfluidic-engineered delivery system for MTX that leverages cyclic arginine-glycine-aspartate (cRGD) peptides to selectively target α v β 3 -integrin, a receptor overexpressed in psoriatic keratinocytes. Using a polydimethylsiloxane (PDMS) microfluidic chip, we synthesised cRGD-conjugated lipid-based nanoparticles (LBNPs) with precise control over their physicochemical properties, achieving monodisperse nanoparticles with a high encapsulation efficiency of over 95 %. The formulation exhibited sustained colloidal stability at 4 °C and demonstrated controlled release, which is critical for prolonged intralesional retention. In vitro evaluation of the formulation on HaCaT cells demonstrated enhanced cellular uptake, driving cytotoxicity, and selective apoptosis (>85 %). In vivo evaluation of the MTX@cRGD LBNPs formulation in imiquimod-induced psoriatic mice demonstrated reduced epidermal hyperplasia and suppressed inflammatory cytokine levels to near baseline levels, outperforming free MTX and non-targeted LBNPs. DIR ex-vivo fluorescence imaging revealed enhanced spreadability at the psoriatic site with no signs of significant accumulation in vital organs, thus mitigating systemic toxicity risks. This platform significantly enhanced targeted MTX delivery by leveraging the high binding affinity of cRGD for α v β 3 -integrin, thereby safely delivering MTX to the target site. Our findings bridge nanotechnology and dermatopathology, offering a translatable blueprint for precision dermatological therapy and chronic inflammatory diseases, which closely aligns with the WHO-2023 directives for safer essential medicines for psoriasis. • Microfluidics enabled one-step synthesis and cRGD functionalisation of MTX liposomes. • MTX@cRGD exhibited pH-responsive release and enhanced cytotoxicity vs. free MTX. • cRGD-liposomes showed selective uptake by αVβ3 psoriatic keratinocytes. • In vivo, cRGD-liposomes accumulated 3× more in psoriatic lesions than non-targeted ones. • Treatment reduced epidermal hyperplasia and IL/TNF-α levels in the IMQ-psoriasis model.