Psoriasis: the scale of the problem and the limitations of current approaches

Psoriasis is a chronic relapsing inflammatory skin disease affecting an estimated 2 to 3% of the global population, ranking among the most prevalent immune-mediated dermatoses. Its most common form — plaque psoriasis — presents as well-demarcated erythematous plaques with silvery scales, most frequently located on the scalp, elbows, and knees. Beyond significant physical discomfort, the disease is frequently accompanied by anxiety and depressive disorders that substantially impair patients' quality of life. It is associated with systemic comorbidities including metabolic syndrome and cardiovascular disease.

The pathogenesis is driven by aberrant keratinocyte proliferation, excessive collagen synthesis by fibroblasts, and infiltration by inflammatory cells — primarily Th1 and Th17 lymphocytes. Macrophages play a central role in initiating and sustaining the inflammatory cascade: they promote T-cell differentiation toward the Th17 phenotype, activate neutrophils, and drive keratinocyte proliferation through secretion of pro-inflammatory cytokines — TNF-α, IL-36γ, and IL-23 [2].

The therapeutic armamentarium for psoriasis is broad — topical corticosteroids, phototherapy, systemic immunosuppressants (methotrexate, cyclosporine), and biologic agents — yet each approach carries significant limitations. Prolonged use of topical steroids leads to skin atrophy; immunosuppressants carry the risk of hepatic and renal toxicity; and biologics, despite high efficacy in some patients, are costly and associated with potentially serious adverse events, including an elevated risk of infections [3]. This underscores the urgent need for new, safer, and more precisely targeted therapeutic strategies — particularly those acting directly on the immune cells that initiate inflammation. Precisely such an approach was proposed by a research team from Peking University and Central South University (China) in a study published in Biomaterials [1].

Emodin and its limitations: why a nanocarrier is needed

Emodin — a natural anthraquinone derived from various medicinal plants (including rhubarb, buckthorn, and knotweed) — has long attracted research attention. It exhibits anti-inflammatory, antioxidant, and immunomodulatory properties and, in experimental studies, has demonstrated the ability to attenuate psoriasis symptoms by suppressing the production of pro-inflammatory cytokines IL-6, IL-23, and TNF-α in macrophages, reducing TNF-α and IL-17 secretion in T cells, and inhibiting keratinocyte proliferation via the STAT3 pathway.

Another property of emodin, identified by the authors in prior work, is equally important: the molecule is a two-photon-excited (TPE) photosensitizer. This means that under excitation by a femtosecond laser at 800 nm, it can generate reactive oxygen species (ROS) and eliminate target cells while simultaneously enabling deep-tissue imaging. These dual capabilities — diagnostics and therapy in one — make emodin a promising candidate for psoriasis treatment [4].

The principal barrier to its clinical application is extremely low water solubility and poor transdermal penetration. To overcome these limitations, the authors developed a liposomal formulation — liposomal emodin (LE). Liposomes — spherical vesicles with a phospholipid bilayer — are widely used in clinical practice owing to their excellent safety profile, biocompatibility, and ability to enhance the bioavailability of hydrophobic molecules [5] dramatically. The optimized liposomes, with a diameter of 100 nm, demonstrated stability across various solvents for at least 7 days and significantly enhanced the two-photon fluorescence properties of the encapsulated emodin.

Two-photon imaging: deeper, more precise, more informative

Fluorescence microscopy is based on a straightforward physical principle: a fluorophore molecule absorbs a photon and transitions to an excited state; upon returning to its ground state, it emits a photon of longer wavelength — the microscope's detector captures this secondary light (fluorescence) to form an image.

In conventional (single-photon) fluorescence microscopy, a short-wavelength laser (~400 nm, near-ultraviolet) is used to excite the fluorophore. Such radiation is strongly scattered and absorbed by tissues, limiting the method to the superficial layers of the skin.

Two-photon laser microscopy operates on a different principle: the molecule is excited not by a single photon but by two photons simultaneously, each carrying half the energy and twice the wavelength (~800 nm, near-infrared). This radiation penetrates tissues considerably more deeply, scatters less, and does not damage surrounding cells. Excitation occurs only within a tiny focal volume where photon density is sufficiently high — providing high spatial resolution and reduced phototoxicity compared with single-photon methods.

Topical application of LE to psoriatic skin lesions in mice substantially enhanced the fluorescence signal, enabling clear visualization of inflammatory cell clusters. The authors also conducted pilot two-photon studies on human skin biopsy samples: fluorescence intensity in psoriatic areas after LE application was significantly higher than in healthy control skin. This points to the method's potential for in vivo diagnostics and dynamic therapy monitoring.

How liposomal emodin works at the cellular level

The therapeutic action of LE unfolds at multiple levels, beginning with the selective accumulation of emodin within macrophages.

• Molecular mechanism: mitochondria of pro-inflammatory macrophages as the target

The therapeutic effect of LE begins with selective accumulation of emodin in macrophages. Liposomes are actively taken up by these cells via scavenger receptors SR-A/MSR1 and SR-BI/CD36 — specialized surface receptors on macrophages that have evolved to recognize and internalize foreign particles, modified lipoproteins, and cellular debris. This feature of macrophage biology confers cellular selectivity on the entire therapeutic approach: LE concentrates in the site of inflammation, leaving keratinocytes and fibroblasts unaffected. Once inside the cell, emodin accumulates in the mitochondria, as confirmed by confocal microscopy with the MitoTracker dye.

Proteomic analysis and molecular docking (computational modeling that predicts how and where a test molecule binds to its target protein) revealed that emodin interacts with subunits of Complex IV (COX4I1) of the mitochondrial electron transport chain (ETC). This interaction disrupts normal ETC function, reduces mitochondrial mass, and suppresses oxidative phosphorylation. The resulting metabolic reprogramming drives a phenotypic switch in macrophages: the pro-inflammatory M1 phenotype is converted to the anti-inflammatory M2 phenotype. In the skin, expression of IL-10 and TGF-β — key anti-inflammatory mediators that suppress T-cell activation and limit the inflammatory cascade — increases, while levels of IL-6, IFN-γ, and IL-17A decline. These three cytokines play a central role in psoriasis pathogenesis: IL-6 and IFN-γ sustain pro-inflammatory macrophage activation and Th1-cell differentiation, while IL-17A — the principal effector cytokine of the Th17 pathway — directly stimulates keratinocyte proliferation and neutrophil recruitment to lesional skin. The observed cytokine shift thus reflects a genuine reprogramming of the skin's immune microenvironment from a pro-inflammatory to an anti-inflammatory state.

Single-cell RNA sequencing (scRNA-seq) data further elaborated this picture. KRT1 and KRT14 are keratin proteins that serve as markers of normal keratinocyte differentiation: KRT14 is characteristic of cells in the basal (deepest) layer of the epidermis, while KRT1 is characteristic of the more superficial differentiated layers. In psoriasis, this order is disrupted: keratinocytes proliferate aberrantly, fail to differentiate properly, and the normal layer-specific distribution of keratins is lost. Under LE treatment, excessive KRT1 expression was reduced, and the ordered distribution of KRT14 was restored, indicating normalization of the keratinocyte differentiation program. In addition, LE inhibited collagen synthesis by fibroblasts and suppressed the pro-inflammatory activity of T lymphocytes.

In parallel, LE reduces expression of the chemoattractant IL-36γ in proliferating macrophages, further blocking T-cell migration and neutrophil recruitment.

• Photodynamic mechanism: TPE-PDT

Upon activation by an 800-nm femtosecond laser, LE generates ROS that induce DNA damage—predominantly in M1 macrophages already saturated with the agent.

This was confirmed by dual immunofluorescence staining using two markers: CD68 — a universal marker of the entire macrophage population — and CD86, which is expressed exclusively on pro-inflammatory M1 macrophages. The analysis showed that before laser irradiation, 24.53% of CD86+ cells already carried the DNA damage marker γH2AX. Following TPE-PDT, both the total number of CD68+ macrophages and the number of CD86+/γH2AX+ cells in psoriatic lesions were significantly reduced.

Analysis of gene expression associated with various cell death mechanisms (ferroptosis, pyroptosis, apoptosis, necroptosis) revealed no significant changes in keratinocytes, further supporting the approach's selectivity.

Results in the psoriasis model

In an imiquimod (IMQ)-induced mouse model of psoriasis, LE treatment — particularly in combination with laser irradiation (TPE-PDT group) — produced the most pronounced clinical effect. Across all parameters of the psoriasis-like severity index (PASI) — erythema, scaling, and infiltration — the IMQ + LE + laser group showed significantly better outcomes than not only the untreated control (IMQ) group but also the LE or laser monotherapy groups. Histologically, lesions showed a marked reduction in epidermal thickness and decreased hyperkeratosis.

Single-cell RNA sequencing data (scRNA-seq — a method that assesses gene activity in individual cells rather than averaging across the entire sample) revealed the cellular basis of these changes:

• in the macrophage population, the proportion of cells expressing M2 surface markers (Mrc1, Cd163, Clec10a — proteins characteristic of the anti-inflammatory phenotype) increased, along with upregulated expression of Socs3, an inhibitor of the JAK-STAT pathway — one of the key signaling cascades sustaining chronic inflammation in psoriasis;
• activity of genes responsible for maintaining the inflammatory microenvironment was suppressed: Cxcr2 and S100a8, involved in neutrophil recruitment to lesional sites, and Il36g, involved in T-cell activation;
• among keratinocytes, the proportion of stressed epidermal stem cells (Stressed EpiSCs) — progenitor cells that shift into a pathological hyperproliferative mode in psoriasis — and proliferating keratinocytes declined, indicating normalization of epidermal architecture, as confirmed by KRT1/KRT14 immunofluorescence staining.

Safety

Topical application of LE or laser irradiation to the normal skin of healthy mice over 6 consecutive days produced no observable changes in skin appearance, epidermal thickness, or degree of keratinization. Biochemical blood analysis and histological examination of internal organs at multiple time points revealed no pathological deviations from normal.

Conclusion

The study published in Biomaterials compellingly demonstrates the multifaceted therapeutic potential of liposomal emodin in psoriasis. By combining, within a single agent, the capabilities of high-resolution two-photon imaging of inflammatory lesions, immune reprogramming of macrophages through mitochondrial ETC modulation, and photodynamic elimination of pro-inflammatory cells, LE offers a fundamentally new treatment concept — targeted and potentially safer than existing systemic approaches.

The study is conceptually noteworthy: a single molecule fulfills three distinct functions:

• immunomodulator — without laser activation, LE reprograms the mitochondrial metabolism of macrophages and normalizes the skin's inflammatory microenvironment;
• contrast agent — enables high-resolution two-photon imaging of inflammatory lesions when applied topically;
• photodynamic agent — selectively eliminates pro-inflammatory M1 macrophages upon laser activation.

This integrated "theranostic" approach — combining diagnostics and therapy in a single agent — aligns with current trends in personalized medicine.

The authors nonetheless acknowledge several limitations. The study was conducted primarily in an animal model; data from human subjects are pilot in nature. Macrophages play a critical role not only in inflammation but also in wound healing and tissue regeneration — particularly the M2 subpopulation, which secretes IL-10 and TGF-β — and the potential impact of LE on reparative processes therefore warrants further investigation. Finally, the depth of LE penetration during TPE-PDT may prove insufficient for deeper forms of involvement — for example, in psoriatic arthritis.

Should these findings be confirmed in controlled clinical trials, liposomal emodin could fill a niche as a safe and accessible agent for topical therapy of plaque psoriasis — both as monotherapy and in combination with a photodynamic component in a specialized clinical setting. Future directions include optimizing application protocols and exploring combination strategies with already-approved agents to enhance its M1-macrophage-specific activity further.

References

1. Sun J., Sun A., Wang Y. et al. Liposomal emodin: a nanomedicine for two-photon imaging and mitochondria-targeted photodynamic therapy of psoriasis. Biomaterials 2026; 325: 123631.
2. Griffiths C.E.M., Armstrong A.W., Gudjonsson J.E., Barker J. Psoriasis. Lancet 2021; 397(10281): 1301–1315.
3. Armstrong A.W., Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: a review. JAMA 2020; 323(19): 1945–1960.
4. Liu Y., Zhao J., Xu X. et al. Emodin-based nanoarchitectonics with giant two-photon absorption for enhanced photodynamic therapy. Angew Chem 2023; 62(33): e202308019.
5. Large D.E., Abdelmessih R.G., Fink E.A., Auguste D.T. Liposome composition in drug delivery design, synthesis, characterization, and clinical application. Adv Drug Deliv Rev 2021; 176: 113651.