Overcoming the cutaneous barrier: Topical delivery platforms for targeted gene-based therapeutics in psoriasis.

Psoriasis is a chronic immune-mediated skin disorder characterized by persistent inflammation, epidermal hyperproliferation, and complex interactions among immune cells, keratinocytes, cytokines, and genetic factors. Although conventional topical agents, systemic small molecules, and biologics have improved disease management, their clinical utility is often limited by insufficient efficacy, adverse effects, treatment resistance, and poor patient adherence. Recent advances in molecular biology have identified numerous pathogenic genes, signaling pathways, and regulatory RNAs involved in psoriasis, providing opportunities for the development of gene-based therapeutics, including antisense oligonucleotides, plasmid DNAs, small interfering RNAs, messenger RNAs, microRNAs, aptamers, and CRISPR/Cas9 systems. These therapeutics enable precise modulation of disease-associated targets at the genomic and transcriptional levels, offering advantages over conventional pharmacological approaches. However, their topical administration is hindered by the formidable cutaneous barrier, limited skin penetration, poor cellular uptake, and susceptibility to enzymatic degradation. This review summarizes the cellular, molecular, and genetic mechanisms underlying psoriasis pathogenesis and discusses the therapeutic potential of diverse gene-based approaches. Particular emphasis is placed on topical delivery platforms designed to overcome cutaneous barriers, including permeation enhancers, nanocarrier-based systems, and physical enhancement technologies. Recent advances in the integration of these delivery strategies with gene therapeutics for targeted psoriasis treatment are highlighted. Finally, current challenges related to delivery efficiency, long-term safety, manufacturing scalability, and regulatory approval are discussed, together with future perspectives for the clinical translation of topical gene-based therapeutics toward precision psoriasis management.