Computer-Designed Peptides Deliver Gene-Silencing Therapy Through the Skin to Treat Psoriasis | Research

The takeaway

Computationally optimized cell-penetrating peptides delivered ADAM17-targeting siRNA through the skin in a spray formulation, suppressing inflammation and improving psoriasis in both human skin models and mice.

Spray-on gene therapy for psoriasis
Computationally designed CPPs in a skin-adhesive spray delivered ADAM17-targeting siRNA through the skin to reprogram the inflammatory environment

What the researchers found

Researchers used computational modeling to design cell-penetrating peptides (CPPs) optimized for transdermal delivery, then loaded them with siRNA targeting ADAM17 — a protein that drives TNF-α-mediated inflammation in psoriasis. The peptide carriers successfully penetrated the skin's stratum corneum, were taken up by immune cells in the dermis, and suppressed ADAM17 expression and TNF-α inflammatory responses.

A skin-adhesive spray formulation containing the peptide-siRNA complexes ameliorated psoriatic pathology in both human 3D skin models and a mouse psoriasis model. Multiplex imaging revealed the peptide carriers reprogrammed immune-epithelial cell cross-talk in the tissue microenvironment.

Why it matters

Psoriasis treatment currently relies on systemic biologics (injected antibodies) or topical steroids. A spray-on peptide carrier that delivers gene-silencing siRNA directly through the skin could offer a non-invasive alternative that targets the root inflammatory cause. The computational optimization approach also demonstrates how AI/computational tools can accelerate peptide carrier design.

How the study worked

Four cationic cell-penetrating peptides were computationally designed and screened for stratum corneum diffusion properties. Therapeutic efficacy was validated in human cell-derived 3D skin models and a murine psoriasis model. A skin-adhesive spray formulation was developed for clinical applicability. ADAM17 downregulation, TNF-α suppression, and inflammatory microenvironment reprogramming were assessed by immunofluorescence, protein expression analysis, and multiplex imaging.

Who was studied

Human 3D skin models and murine psoriasis model

What this study cannot tell us

Preclinical study using 3D skin models and mouse psoriasis models — human clinical efficacy is unknown. The translation from computational predictions to actual transdermal penetration in human skin may differ. Long-term safety of repeated transdermal siRNA/peptide carrier application is not assessed. The psoriasis model may not fully replicate human disease complexity.

How to read the evidence

This is a preliminary-grade preclinical study with a strong translational approach — combining computational design, 3D human skin models, and animal validation. However, human clinical trials are needed to confirm safety and efficacy.

When this study was published

Published in 2026, this is cutting-edge research at the intersection of computational peptide design, RNA therapeutics, and dermatology.

The bigger picture

Cell-penetrating peptides represent a growing class of drug delivery vehicles capable of transporting therapeutics across biological barriers. This study combines two cutting-edge approaches — computational peptide design and siRNA gene therapy — into a practical topical formulation. If successful in humans, it could disrupt the psoriasis treatment market and serve as a platform for delivering gene therapies for other skin conditions.

Questions still open

How does the transdermal penetration efficiency compare between the computationally optimized CPPs and existing cell-penetrating peptides like TAT or penetratin?
Could this peptide-siRNA spray platform be adapted for other inflammatory skin diseases like eczema or lupus skin lesions?
What is the durability of ADAM17 knockdown from a single application — how often would the spray need to be reapplied?

Common questions

What are cell-penetrating peptides and how do they cross the skin?

Cell-penetrating peptides (CPPs) are short, positively charged peptides that can pass through cell membranes and tissue barriers that normally block drug entry. In this study, CPPs were computationally optimized to diffuse through the stratum corneum — the tough outer layer of skin — carrying siRNA payloads into the underlying tissue where immune cells take them up.

How is this different from current psoriasis treatments?

Current topical treatments (like steroids) manage symptoms but don't target the molecular cause. Injectable biologics (like TNF-α blockers) are effective but require needles and are expensive. This spray delivers siRNA that silences ADAM17 — a key driver of the inflammatory cascade — directly through the skin, potentially offering targeted molecular therapy without injections.

Read the original research

In silico optimized cell-penetrating peptides achieve transdermal siRNA delivery and regulate inflammatory environment in psoriasis.

Biomaterials, 328, 123882

View on PubMed ↗Publisher’s paper ↗

Citation

Wang, Yefeng; Wu, Siwen; He, Yilin; Zhang, Jiani; Chen, Yujiao; Zhou, Lei; Li, Xiaopeng; Yang, Li. (2026). In silico optimized cell-penetrating peptides achieve transdermal siRNA delivery and regulate inflammatory environment in psoriasis.. Biomaterials, 328, 123882. https://doi.org/10.1016/j.biomaterials.2025.123882