A design framework for skin-targeted RNA nanomedicines: spatial reprogramming of immune memory in psoriasis.

Biologics targeting TNF-α, IL-23, or IL-17 clear psoriatic plaques effectively, yet lesions recur at the same anatomical sites upon treatment withdrawal. This is not a failure of potency but of target: the tissue-encoded immune memory that sustains site-specific relapse remains largely inaccessible to systemic cytokine blockade. This perspective proposes a design-first framework for skin-targeted RNA nanomedicines that translates this biological insight into concrete engineering requirements. Five immune nodes, tissue-resident memory T cells (TRM), regulatory T cells, dendritic cells, stromal-vascular niches, and cutaneous neuroimmune circuits, sustain psoriatic persistence across defined compartments of the plaque, and each is, in principle, addressable through RNA payloads delivered via dissolvable polymer microneedle arrays. The framework is organised around three design dimensions: where payloads must be deposited, what molecular instructions they must carry, and when delivery must be sequenced across a three-phase temporal model of suppression, tolerisation, and maintenance. A translational roadmap addresses regulatory classification, chemistry-manufacturing-and-controls, psoriasis-specific immunotoxicology, and adaptive within-patient trial designs anchored to mechanistic biomarkers. The framework is presented as a design hypothesis grounded in mechanistic evidence; empirical validation in human psoriatic skin is outlined as the next translational step.