Smart nanodelivery of palmitoylethanolamide for topical treatment of inflammatory skin diseases

Palmitoylethanolamide (PEA) is an endogenous lipid mediator with well-documented anti-inflammatory activity mediated by PPAR-α activation [1]. Despite its therapeutic potential, topical application of PEA is strongly limited by its poor aqueous solubility, high lipophilicity and inadequate skin penetration. Innovative drug delivery strategies are therefore required to unlock its clinical efficacy in inflammatory skin diseases such as psoriasis. We developed a novel non-mechanical nanonization approach to obtain a nanostructure form of PEA (Nano-PEA), based on a displacement solvent process [2]. Nano-PEA was extensively characterized in terms of particle size, morphology, surface charge, stability, solubility, partition coefficient and in vitro dissolution. Skin permeation was evaluated using Franz diffusion cells and Strat-M® artificial membranes. Cellular uptake and anti- inflammatory activity were investigated in murine J774 macrophages. In vivo efficacy was assessed in an imiquimod-induced psoriasis-like mouse model (C57bl/6, 8-week-old females) following topical application of Nano-PEA included in an almond oil-based cream, compared with placebo, pure PEA and betamethasone dipropionate. Nano-PEA formed stable, spherical nanoparticles (~230 nm, PDI <0.3) with a moderately negative surface charge and preserved physicochemical stability over time. Nanonization markedly increased PEA solubility, reduced its lipophilicity (Log P ≈ 0), and enhanced dissolution rate compared to crystalline PEA. In vitro permeation studies demonstrated significantly higher and faster skin penetration of Nano-PEA, particularly at early time points, resulting in increased permeability coefficients. Nano-PEA was efficiently internalized by macrophages, showing superior uptake and a broader anti-inflammatory cytokine modulation compared with pure PEA, without inducing cytotoxicity. In vivo, topical Nano-PEA significantly reduced erythema, scaling, epidermal thickness and cumulative PASI score, with efficacy comparable to topical corticosteroids. This clinical improvement correlated with a marked inhibition of key psoriasis-driving cytokines (IL- 23, IL-17A and TNF-α) directly at the lesion site [3]. This study provides a comprehensive proof-of-concept that smart nanodelivery can transform PEA into an effective topical anti-inflammatory therapy. By overcoming intrinsic bioavailability limitations, Nano-PEA represents a promising non-steroidal drug delivery platform for the treatment of inflammatory skin diseases.