Phytochemical-Loaded Nanodelivery Systems for Skin-Targeted Immunomodulation in Psoriasis and Atopic Dermatitis: Mechanistic Insights, Delivery Challenges, and Translational Perspectives

Psoriasis and atopic dermatitis are chronic inflammatory skin diseases with long-term therapeutic needs. Current treatments are effective, but their continuous use can be limited by tolerability and safety concerns. Plant-derived bioactive compounds offer immunomodulatory potential; however, their clinical use is restricted by poor solubility and instability, as well as insufficient delivery into diseased skin. Nanoformulation can address these delivery limitations by improving phytochemical stability, cutaneous deposition, retention, and penetration where appropriate. This improvement becomes more meaningful when the carrier, the active compound, the disease-specific barrier structure, and the dominant immunological targets are aligned. The review focuses on topically applied phytochemical-loaded nanodelivery systems, while conventional phytochemical studies are considered only to contextualize their underlying pharmacology and immunomodulatory mechanisms. In psoriasis, the thick and compact barrier of hyperkeratotic plaques creates a need for penetration-enhancing systems. Curcumin- and indigo-naturalis-derived preparations have relatively developed evidence in psoriasis, although evidence specifically supporting their nanoformulated forms remains predominantly preclinical. Altered barrier integrity in atopic dermatitis may vary the optimal delivery strategy due to anatomical site, disease severity, therapeutic target, and the skin compartment requiring drug exposure. Therefore, it is important to consider the controlled drug deposition and skin compatibility alongside penetration enhancement. Across both diseases, NF-κB and STAT signaling pathways deliver overlapping therapeutic targets. However, the prime immune responses like Th17/IL-23 and type 2/Th2 signaling are particularly prominent for psoriasis and dermatitis, respectively. The translational gap is clearer in atopic dermatitis, where the reviewed systems have not yet been evaluated in randomized controlled trials with validated endpoints. For psoriasis, some phytochemical interventions have reached clinical evaluation, but clinical evidence specifically for nanoformulated phytochemicals remains limited. Further progress requires endotype-informed trial design, biomarker-stratified patient selection, and mechanistic endpoints beyond cytokine suppression.