Psoriasis is a chronic autoimmune skin disease driven by immune system dysregulation and is pathologically characterized by epidermal keratinocyte hyperproliferation, dermal vasodilation, and T cell-dominated immune cell infiltration [1,2]. Patients typically present with well-demarcated erythematous plaques covered by silvery-white scales, often accompanied by pruritus, burning pain, or joint swelling. Notably, psoriasis extends beyond cutaneous manifestations, contributing to systemic inflammation that underlies comorbidities such as psoriatic arthritis, cardiovascular disease, type 2 diabetes, and depression [3]. Epidemiologic studies indicated a decline in global incidence of psoriasis from 1990 to 2019, with substantial geographic variation ranging from 0.1 % in East Asia to 1.5 % in Western Europe [[4], [5], [6], [7]]. The profound impact of psoriasis on quality of life, spanning physical discomfort, psychological distress, and social stigmatization, underscores the urgent need for targeted strategies to manage its evolving burden across diverse populations [8].

A core clinical challenge in psoriasis management is its persistent recurrence. Even following successful therapeutic intervention and lesion regression, the disease frequently reappears at original or adjacent sites. Recent research has established tissue-resident memory T (TRM) cells as pivotal drivers of this recurrent phenotype [9]. These cells persist within barrier tissues, such as the skin, long after initial inflammation resolves, without re-entering systemic circulation. Upon re-exposure to cognate antigen or local inflammatory stimuli, TRM cells undergo rapid activation, proliferation, and robust secretion of pro-inflammatory cytokines (e.g., IFN-γ, IL-17) [10,11], functioning as key effector cells responsible for local psoriatic relapse. Evidence confirms that sufficient generation and persistence of cutaneous TRM populations are strictly dependent on IL-15 signaling. IL-15 primarily produced by keratinocytes, dendritic cells, and other stromal and immune cells, binds to its cognate receptor (IL-15Rα/βγc) to deliver critical survival signals essential for long-term TRM cell residency within tissues. The first cell type to be implicated as a functionally relevant source of IL-15 in the context of the immune response was members of the monocyte/macrophage lineage [12,13]. Other APCs, such as blood-derived dendritic cells, have been shown to produce IL-15 mRNA and protein, suggesting a role in the attraction and stimulation of T cells [14,15].

In fact, tumor necrosis factor-alpha (TNF-α) can regulate IL-15 via NF-κB signaling. Ouyang et al. revealed that TNF-α alters the trafficking dynamics of IL-15 and IL-15Rα, leading to enhancement of IL-15 secretion by increasing nucleus export of its ligand-receptor complex [16]. It has been reported that both transcriptional control of IL-15 and IL-15 regulation appear to be pivotal to IL-15 protein production [17,18]. On one hand, TNF-α-TNFR binding can activate IKK, degrading IκBα and triggering NF-κB nucleus translocation [19]. On the other hand, phosphorylated NF-κB translocates into nucleus and binds to the IL-15 promoter (position −75/−65), consequently leading to IL-15 upregulation [20,21]. Collectively, these findings supported the hypothesis that elevated TNF-α binding to its receptors activates NF-κB signaling, inducing IL-15 production and promoting TRM cell prevalence. Therefore, blockade of TNF-α-TNFR signaling, by suppressing cutaneous IL-15-mediated TRM cell survival, maintenance, and reactivation, may represent a promising strategy for preventing psoriasis recurrence.

Current therapeutic approaches for psoriasis treatment include topical therapies (e.g., glucocorticoid ointments, vitamin D3 analogs) for mild lesions, phototherapy (e.g., narrowband-UVB) for moderate-to-severe plaque psoriasis unresponsive to topicals, systemic immunosuppressants (e.g., methotrexate, cyclosporine) or small-molecule agents for refractory cases, and biologics (e.g., TNF-α/IL-17/23 inhibitors) for moderate-to-severe disease or treatment failures [[22], [23], [24], [25]]. Despite these therapeutic advances, adverse effects, relapse rates, and limited efficacy (observed in ∼30 % of moderate-to-severe cases) due to hepatorenal toxicity or intolerance remain unresolved challenges [26]. These therapeutic limitations highlight the urgent need for alternative interventions capable of inducing long-term remission while maintaining an improved safety profile. TNF-α, a pro-inflammatory cytokine predominantly secreted by macrophages, dendritic cells, and T cells, plays a central role in psoriasis pathogenesis by driving inflammation, vascular adhesion molecule upregulation, and inflammatory cell recruitment, while amplifying IL-17-mediated pathological effects [27].

Etanercept, a recombinant fusion protein-based TNF-α inhibitor comprising the extracellular domain of human TNF receptor p75 and the Fc segment of IgG1, neutralizes soluble TNF-α and lymphotoxin-α (LT-α). This disrupts TNF-TNFR interactions and suppresses inflammatory cascades [28,29]. Monoclonal antibodies such as Infliximab and Adalimumab similarly neutralize TNF-α, demonstrating broader immunomodulation than IL-17/IL-23 inhibitors [30,31]. These agents mitigate epidermal hyperplasia through diminished IFN-γ/IL-17 secretion, attenuate neutrophil infiltration by limiting elastase/myeloperoxidase release, and downregulate endothelial ICAM-1/VCAM-1 expression to curb leukocyte extravasation [32]. TNF-α–TNFR blockade also resolves psoriatic skin pathology and ameliorates systemic comorbidities, including psoriatic arthritis and Crohn's disease, supporting approval for these indications [33]. TNF-α inhibitor therapy reduces TRM cell marker expression (CD103, CD69, CD49, CXCR6). Although not universally curative, sustained disease control is observed after therapy cessation compared to other treatments, suggesting potential disease-modifying effects [34].

Despite robust clinical validation (>20-year safety data) and systemic anti-inflammatory synergy in metabolic/ocular comorbidities, limitations persist: frequent dosing (2–3-week half-life), secondary failure (10–20 % of cases due to immunogenicity or suboptimal drug levels), and risks of infections (tuberculosis, fungal) or heart failure [[35], [36], [37]]. These shortcomings highlight the need for next-generation TNF-α inhibitors with enhanced durability, localized action, and reduced immunogenicity. Emerging mRNA technologies offer a transformative approach to addressing these limitations of current psoriasis therapies [38]. Codon-optimized, chemically modified mRNAs enable endogenous production of therapeutic proteins with accurate post-translational modifications unattainable via conventional recombinant systems [39]. mRNA synthesis via in vitro transcription allows rapid customization and scalability, while the interplay of sequence, modification, and structure dictates mRNA stability and translation [40,41]. However, clinical translation has been hindered by mRNA instability and cutaneous delivery challenges imposed by the stratum corneum barrier [42]. Lipid nanoparticles (LNPs), currently the most mature non-viral delivery system [38], have successfully addressed these limitations and show great promise for dermatological applications [43].

To address the limitations of systemic administration and frequent relapse, this study reported a localized, TNF-α-targeting mRNA therapeutic LNP, namely RET-1-mRNA-LNP and we evaluated its efficacy and explored its mechanism of action in a psoriasis relapse model. This strategy circumvents systemic off-target effects through localized action while enabling sustained therapeutic protein expression. Notably, RET-1-mRNA-LNP-mediated inhibition of TNF-α suppresses IL-15 expression, thereby attenuating the maintenance of dermal tissue-resident memory T (TRM) cells. By maintaining prolonged efficacy and minimizing immunogenicity, RET-1-mRNA-LNP represents an innovative strategy to address psoriasis relapse and systemic toxicity, with potential applications for autoimmune diseases requiring precision and long-term immune modulation (Scheme 1).