Psoriasis is a chronic inflammatory disease affecting 2% of the global population. Current treatments (e.g., corticosteroids and phototherapy) face limitations such as adverse effects and poor bioavailability, necessitating safer, more effective alternatives. Pomegranate (Punica granatum L.) peel, rich in bioactive compounds with antioxidant and anti-inflammatory properties, holds therapeutic potential but suffers from low stability and solubility. Here, we developed pomegranate peel extract nanoparticles (PGNPs) to overcome these limitations and evaluated their efficacy in psoriasis management. Pomegranate peel extract (PGE) was prepared and transformed into PGNPs via acid hydrolysis. Nanoparticles were characterized for size, stability, and bioactivity. In vitro assays assessed cytotoxicity, antioxidant (DPPH), and anti-inflammatory (hemolysis inhibition) effects. In vivo efficacy was tested in imiquimod-induced psoriatic rats (n = 20) divided into negative control (group I), untreated psoriasis (group II), PGE-treated (200 mg/kg, group III), and PGNPs-treated (100 mg/kg, group IV). Outcomes included oxidative stress markers (MDA, SOD, CAT, and GSH), cytokines (IL-6, IL-17, IFN-γ, and IL-10), and histopathology. PGNPs exhibited superior stability (size: 87–91 nm; zeta potential: +41–44 mV) and lower cytotoxicity than PGE (15.2% vs. 31.2% at 1000 µg/mL). In vitro, PGNPs showed higher antioxidant (96.63% DPPH scavenging) and anti-inflammatory (94.66% hemolysis inhibition) activity. In vivo, PGNPs reduced psoriatic lesions more effectively than PGE, normalizing oxidative stress (MDA: 7.26 vs. 12.22 nmol/g tissue) and inflammatory cytokines (IL-17: 102.20 vs. 123.40 pg/g tissue; IFN-γ: 204.40 vs. 216.80 pg/g tissue). Histopathology confirmed enhanced skin regeneration with PGNPs. PGNPs demonstrated enhanced bioavailability, stability, and therapeutic efficacy over crude extract, significantly mitigating psoriasis-like inflammation in rats. These findings highlight PGNPs as a promising nanotherapy for psoriasis, warranting further clinical exploration.
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