Coating Janus Nanoparticles with Immunoregulatory Protein Embedded Membrane for Enhanced Anti‐Inflammatory and Sonodynamic Therapy of Psoriasis

Abstract The interplay between keratinocyte (KC) hyperproliferation and T cell activation underpins psoriasis pathogenesis, posing significant challenges for effective treatment. Here, cell membrane‐coated nanoparticles (CNPs) are designed to simultaneously inhibit T cell activation and KC hyperproliferation for optimized psoriasis therapy. A customized cell membrane is genetically engineered to overexpress the immunoregulatory V‐domain immunoglobulin suppressor of T cell activation (VISTA) protein to enable potent T‐cell inhibition. The encapsulated core is designed as Janus nanoparticles (mSiO 2 &rPMO) for co‐delivery of hydrophilic 5‐aminolevulinic acid (5‐ALA) and hydrophobic tazarotene, facilitating synergistic sonodynamic therapy (SDT) and anti‐inflammatory effects. Mechanistically, under ultrasound stimulation, accumulated protoporphyrin IX (PpIX) derived from 5‐ALA metabolism generates reactive oxygen species (ROS) that inhibit epidermal proliferation, while tazarotene activates retinoic acid receptor gamma (RARγ) to exert anti‐inflammatory effects. Concurrently, the VISTA‐overexpressed membrane enhances anti‐inflammatory responses, further amplifying the anti‐psoriatic effect. CNP efficacy in a psoriatic mouse model is validated, demonstrating mitigated lesion severity, suppressed epidermal hyperplasia, and reduced inflammatory cytokine levels in skin lesions. Notably, CNPs outperformed non‐membrane counterparts in both cellular and animal models, highlighting the anti‐psoriatic amplification conferred by the engineered membrane. Overall, this research presents a novel therapeutic strategy for psoriasis management using engineered membrane‐coated mesoporous Janus nanoparticles to target keratinocyte proliferation and T cell activation.